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CANCER ETIOLOGY, DIAGNOSIS AND TREATMENTS

PHARMACOLOGY - RESEARCH, SAFETY TESTING AND REGULATION

THE EASY BOOK OF


CANCER PHARMACOLOGY

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CANCER ETIOLOGY, DIAGNOSIS
AND TREATMENTS
PHARMACOLOGY - RESEARCH, SAFETY
TESTING AND REGULATION

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CANCER ETIOLOGY, DIAGNOSIS AND TREATMENTS
PHARMACOLOGY - RESEARCH, SAFETY TESTING AND REGULATION

THE EASY BOOK OF


CANCER PHARMACOLOGY

ESTHER UNA CIDON


EDITOR

New York
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Published by Nova Science Publishers, Inc. † New York


CONTENTS

Foreword ix
F. Lopez-Lara
Preface xi
®
Chapter 1 Abiraterone: Abiraterone Acetate: CB7630: Zytiga 1
A. Ballesteros
Chapter 2 Albumin-Bound (NAB) Paclitaxel, Abraxane® 7
V. Arrazubi, E. Galve and P. Martínez del Prado
Chapter 3 Aflibercept. Zaltrap® 19
M. López-Gómez, B. García de Santiago, E. Jiménez,
A. M. Jiménez-Gordo and E. Casado
Chapter 4 Axitinib. Inlyta® 29
A. Ballesteros
Chapter 5 Bevacizumab. Avastin® 37
M. López-Gómez, B. García de Santiago, A. I. García,
A. M. Jiménez-Gordo and E. Casado
Chapter 6 Bleomycin. Bleo-Kyowa. Blenoxane 49
B. Masters
Chapter 7 Cabazitaxel. Jevtana® 59
E. Una Cidon
Chapter 8 Cabozantinib (XL184). Cometriq® 67
J. Molina Cerrillo, M. Gion Cortés, T. Alonso-Gordoa
and E. Grande-Pulido
Chapter 9 Capecitabina. Xeloda® 77
P. Diezhandino and P. Alonso
Chapter 10 Carboplatin. Paraplatin®. CBDCA. Diammineplatinum (II).
Cis-(1,1.Cyclobutanedicarboxylato).
Cis-Diammine (1,1-Cyclobutanediocarboxylato) Platinum 85
M. Luque Cabal and P. Garcia Teijido
vi Contents

Chapter 11 Cetuximab. Erbitux® 95


M. López-Gómez, B. García de Santiago, Y. Martín,
A. M. Jiménez-Gordo and E. Casado
Chapter 12 Cisplatin, Platinol®, Platinol®-AQ 103
M. Luque Cabal and P. Garcia Teijido
Chapter 13 Crizotinib. Xalkori® 113
V. Wood
Chapter 14 Cytarabine: Ara-C: Cytosar U: Cytosine Arabinoside:
Tarabine PFS, Arabinosylcytosine, 1-Β-Arabinosylcytosine 123
T. Cummin
Chapter 15 Denosumab, Prolia®, Xgeva® 131
P. Alonso and P. Diezhandino
Chapter 16 Docetaxel.Taxotere® 139
E. Galve, V. Arrazubi,
P. Martínez del Prado and E. Una Cidon
Chapter 17 Doxorubicin Hydrochloride. Adriamycin 147
Z. Anwar
Chapter 18 Enzalutamide. Xtandi®. MVD3100 157
J. Ching
Chapter 19 Erlotinib, Tarceva® 165
S. Adeleke
Chapter 20 Etoposide: VP16: Vepesid: Etopophos 173
Z. Anwar
Chapter 21 Everolimus. Afinitor® 181
Y. Inam
Chapter 22 Gefitinib 189
S. Adeleke
Chapter 23 Gemcitabine. Gemzar® 197
P. Martínez del Prado, E. Galve and V. Arrazubi
Chapter 24 Imatinib. Gleevec® 207
A. Ballesteros
Chapter 25 Ipilimumab 219
J. Fra
Chapter 26 Irinotecan.CPT-11. Camptosar® 227
E. Una Cidon
Chapter 27 Lapatinib 235
V. Reguero Cuervo, T. Sampedro Gimeno
and P. García Teijido
Contents vii

Chapter 28 Lenvatinib, Lenvima® 249


O. Martínez-Sáez, A. Madariaga-Urrutia,
T. Alonso-Gordoa and E. Grande-Pulido
Chapter 29 Mitomycin C Mitomycin-C Kyowa [3], Mutamycin, Ametycine,
Mitocin-C, Mitolem, Mito-Medac [1] Mitosol [12] 257
M. Uherek
Chapter 30 Nindetanib. Vargatef® 267
E. Una Cidon
Chapter 31 Nivolumab. Opdivo® 273
E. Una Cidon
Chapter 32 Oxaliplatin. 1-OHP, L-OHP, Oxalatoplatin,
Oxaliplatinum, Eloxatin® 281
M. Luque Cabal and P. Garcia Teijido
Chapter 33 Paclitaxel: Taxol 291
E. Una Cidon and A. Ballesteros
Chapter 34 Panitumumab. Vectibix® 299
M. López-Gómez, B. García de Santiago,
R. Hernández, A. M. Jiménez-Gordo and E. Casado
Chapter 35 Pazopanib. Votrient® 307
A. Hernandez-Sanchez
Chapter 36 Pembrolizumab. Keytruda® 317
E. Una Cidon
Chapter 37 Pemetrexed. Alimta® 327
M. Uherek
Chapter 38 Pertuzumab. Perjeta 337
T. Sampedro Gimeno, V. Reguero Cuervo
and P. Garcia-Teijido
Chapter 39 Regorafenib. Stivarga® 349
M. López-Gómez, B. García de Santiago, C. Martín,
M. Caridad Miguel and E. Casado
Chapter 40 Sorafenib, Nexavar® 359
E. Una Cidon
Chapter 41 Streptozocin. Zanosar® 367
V. Wood
Chapter 42 Sunitinib. Sutent® 375
S. Adeleke
Chapter 43 Trastuzumab Emtansine (TDM-1) 385
P. Garcia-Teijido, T. Sampedro Gimeno,
V. Reguero Cuervo and M. Luque Cabal
viii Contents

Chapter 44 Temozolomide. Temodal®. Temodar®. Schs2.365. Nsc 362856 395


J. Ching
Chapter 45 Temsirolimus. CCI-779. Torisel® 405
J. M. Roca
Chapter 46 Topotecan, Hycamtin® 415
J. M. Roca
Chapter 47 Trastuzumab. Herceptin® 425
P. Garcia-Teijido, T. Sampedro Gimeno,
V. Reguero Cuervo and M. Luque Cabal
Chapter 48 Vandetanib (ZD 6474). Caprelsa 435
P. Reguera Puertas, M. Villamayor Delgado,
T. Alonso Gordoa and E Grande Pulido
Chapter 49 Vemurafenib. Zelboraf® 445
A. Hernandez-Sanchez
Chapter 50 Vinorelbine. Navelbine® 457
B. Masters
Chapter 51 Zoledronic Acid, Zometa®, Aclasta®, Reclast® 469
P. Alonso and P. Diezhandino
Chapter 52 5-Fluorouracil, 5-Fluracil, Fluorouracil, Fu 479
P. Diezhandino and P. Alonso
Editor's Contact Information 487
Index 489
FOREWORD

The Easy Book of Cancer Pharmacology is a practical and updated guide to the
antitumor drugs. The chapters of the book explain the general data of each drug used as an
antineoplastic in a very simple way. The book is easy to understand and allows an immediate
knowledge about the details of each drug and a prompt diagnosis of the side effects and their
management.
The editor and author, Dr. Esther Una Cidon, is a competent and brilliant medical
oncologist, trained in Spain, and with who I have been honoured to work for a few years at
the Clinical University Hospital of Valladolid. She is notorious for her strong clinical
experience, continuous updating and scientific rigor. Her professional activity extends to
clinical research and, as this book shows, teaching.
The book is primarily aimed at residents and registrars in oncology, specialist in
oncology nurse practitioners, young consultants in oncology and cancer clinical
pharmacologists, and provides them with valuable information. Due to its facility and
accuracy, this guide will be an essential tool for the target audience as it incorporates the
latest news and updates in the dynamic field of cancer pharmacology.

Prof. F. Lopez-Lara
Director of the Department. Of Clinical Oncology
Clinical University Hospital of Valladolid, Spain
PREFACE

The Easy Book of Cancer Pharmacology represents the efforts of young oncologists,
haematologists, pharmacists and oncology nurses who are highly motivated and encouraged
by the significant development of new effective anticancer drugs.
Since the discovery of antimetabolites and alkylating agents in the 1940s and 1950s,
many new products have been introduced into our daily arsenal not only through
chemotherapy agents, but also by means of biological or immunotherapeutic drugs whose
side effects differ significantly.
The idea of this book was born from a simple observation and confirmation of fact. New
doctors in training experience high levels of stress and lack of confidence when confronting
cancer patients and explaining a treatment or managing frequent side effects. Patients‘
questions will only add more nervousness, and this will lead to a failure in the doctor-patient
relationship, causing the patient‘s mistrust and doctor‘s frustration. Nurses dealing with these
patients will suffer pressure too, as many questions regarding antineoplastic drugs will be
asked of them and patients expect them to ease their doubts. This feeling of vulnerability in
front of a patient, though a part of the maturation process when becoming a professional
caretaker, causes discomfort and incertitude.
In this context, it is crucial to gain great knowledge about pharmacokinetic and
pharmacological features of each active anticancer drug used, as well as the indications,
dosages, interactions and toxicities, to be able to face the daily practice of oncology without
concerns and manage daily therapeutic complications easily.
This may be considered very difficult, taking into account the huge number of active
agents doctors manage routinely, but doctors have accepted the challenge and designed a
straightforward, comprehensible book to solve this issue. The Easy Book of Cancer
Pharmacology provides the means to overcome the problem. It is conceived as an accessible,
concise and yet exhaustive tool which displays a vast amounts of knowledge in a very
schematic way. It is easy to consult and offers a very practical expertise to develop the ability
of managing effectively each antineoplastic agent quickly. It gives the necessary insights to
explain this to the patients with confidence.
Each chapter reviews one active drug and shows the information with a pragmatic style,
and they are divided into different sections. Each section covers distinct aspects of the agent,
from general characteristics to more specific details related to clinical pharmacology.
xii Esther Una Cidon

In quickly advancing fields such as oncology, tools like this book are necessary to help
update the ever developing knowledge in an efficient manner.
The authors are greatly appreciated for their invaluable collaboration and for having
respected the spirit with which this book was written.

Esther Una Cidon, MD, PhD


Medical Oncologist
Medical Oncology Department
Royal Bournemouth Hospital NHS Foundation Trust
Bournemouth, UK
To my parents, my two sisters and my uncle P.
for their great support throughout my career
and also in the preparation of this book

I dedicate this book to them and to those who always believed in me


In: The Easy Book of Cancer Pharmacology ISBN: 978-1-63485-038-4
Editor: Esther Una Cidon © 2016 Nova Science Publishers, Inc.

Chapter 1

ABIRATERONE: ABIRATERONE ACETATE:


CB7630: ZYTIGA®

A. Ballesteros
Directorate Pharmacist, Oncology, Poole Hospital Foundation Trust, Poole, Dorset, UK

ABSTRACT
Abiraterone inhibits 17 α-hydroxylase/C17, 20 lyase (CYP17A1), an enzyme which
is expressed in testicular, adrenal, and prostatic tumor tissues which leads to a reduction
in circulating levels of testosterone.
Androgen-sensitive prostatic carcinoma responds to treatment that decreases
androgen levels. Androgen deprivation therapies, such as treatment with luteinizing
hormone-releasing hormone analogues (LHRH) or orchiectomy, decrease androgen
production in the testes but do not affect androgen production by the adrenals or in the
tumour. Treatment with Zytiga® decreases serum testosterone to undetectable levels
(using commercial assays) when given with LHRH (or orchiectomy) [1].
In 2011 the Food and Drug Administration (FDA) approved abiraterone acetate for
use in combination with prednisone for the treatment of patients with metastatic
castration-resistant prostate cancer (mCRPC) who have received prior chemotherapy
containing docetaxel. This approval was based on the results of a randomized placebo-
controlled multicenter trial which demonstrated a statistically significant improvement in
overall survival in patients receiving abiraterone acetate compared with placebo.
In 2012 the FDA approved an expanded indication for the treatment of mCRPC
based on a trial that randomly assigned patients with mCRPC naïve for chemotherapy to
either abiraterone plus prednisone or placebo plus prednisone. Entry was restricted to
patients with metastases to the bone, soft tissue, or lymph nodes. Patients with moderate
to severe cancer pain or opiate use for cancer pain were excluded. All patients had a prior
orchiectomy or continued to receive a gonadotropin releasing hormone analog.
Radiographic progression-free survival (rPFS) was improved significantly by abiraterone.
Median overall survival at the pre-specified third interim analysis was 35.3 months for
abiraterone acetate and 30.1 months for placebo though not statistically significant [2].


Alejandro Ballesteros, entoatucass@googlemail.com.
2 A. Ballesteros

Keywords: abiraterone, prostate cancer, castration resistant prostate cancer

INTRODUCTION
Abiraterone is a structural analogue of pregnenolone (steroidal hormone manufactured
primarily in the adrenal glands from its precursor, cholesterol with a number of beneficial
effects) which inhibits an enzyme necessary for androgen synthesis, 17α-hydroxylase/C17,
20-lyase (CYP17) that is expressed in testicular, prostate, and adrenal tissue. It is approved
for the treatment of mCRPC in patients asymptomatic or mildly symptomatic after failure of
androgen deprivation therapy or patients who have progressed on docetaxel [3].
Although the activity of abiraterone is primarily confined to effects on androgen
production, there is a reactive increase in corticotropin secondary to a pituitary response to
the partial adrenal inhibition, which can lead to increased mineralocorticoid production. This
can lead to hypokalemia and hypertension, which can be reduced by concurrent prednisone
administration [2].

CLINICAL PHARMACOLOGY
Drug Classification

Endocrine therapy, other hormone antagonists and related agents [2].

Mechanism of Action

Abiraterone inhibits 17 α-hydroxylase/C17,20 lyase (CYP17A1), an enzyme which is


expressed in testicular, adrenal, and prostatic tumour tissues. CYP17 catalyses two sequential
reactions: (a) the conversion of pregnenolone and progesterone to their 17-α-hydroxy
derivatives by its 17 α-hydroxylase activity, and (b) the subsequent formation of
dehydroepiandrosterone (DHEA) and androstenedione, respectively, by its C17,20 lyase
activity [9]. DHEA and androstenedione are androgens and precursors of testosterone.
Inhibition of CYP17 activity by abiraterone thus decreases circulating levels of testosterone
[3].
Androgen-sensitive prostatic carcinoma responds to treatment that decreases androgen
levels. Androgen deprivation therapies, such as treatment with LHRH analogues or
orchiectomy, decrease androgen production in the testes but do not affect androgen
production by the adrenals or in the tumour. Treatment with abiraterone decreases serum
testosterone to undetectable levels (using commercial assays) when given with LHRH
analogues (or orchidectomy) [2].
Abiraterone: Abiraterone Acetate 3

Pharmacokinetics [2]

Absorption Time to reach maximum plasma concentration is approximately 2 hours.


Administration of abiraterone acetate with food, compared with administration
in a fasted state, results in up to a 10-fold (AUC) and up to a 17-fold (Cmax)
increase in mean systemic exposure of abiraterone, depending on the fat content
of the meal. Given the normal variation in the content and composition of meals,
taking Zytiga with meals has the potential to result in highly variable exposures.
Therefore, Zytiga must not be taken with food. It should be taken at least two
hours after eating and no food should be eaten for at least one hour after taking
Zytiga. The tablets should be swallowed whole with water.
Distribution The plasma protein binding of 14C-abiraterone in human plasma is 99.8%. The
apparent volume of distribution is approximately 5,630 l, suggesting that
abiraterone extensively distributes to peripheral tissues.
Metabolism Liver metabolism due to cytochrome CYP3A4
Excretion Mean half-life 15 hours. Excreted mostly in faeces (88%)

Mechanism of Resistance

Increase on intratumoral androgen synthesis and increased expression of full length and
split variants of the androgen receptor [2].

Indications [2]

Abiraterone indications are as follows:

 The treatment of mCRPC in adult men who are asymptomatic or mildly symptomatic
after failure of androgen deprivation therapy in whom chemotherapy is not yet
clinically indicated.
 The treatment of mCRPC in adult men whose disease has progressed on or after a
docetaxel-based chemotherapy regimen.

Dosages

Abiraterone is available as 250 mg tablets and is administered at a dose of 1000 mg daily


in combination with prednisone 5 mg administered twice daily [2].

Methods of Preparation/Administration

Tablets should be taken whole, swallowed with water and on an empty stomach, with no
food for 2 hours before and 1 hour after administration [2].
4 A. Ballesteros

Special Information and Cautions [2]

Contraindications

 Hypersensitivity to the active substance or to any of the excipients listed below.


 Microcrystalline cellulose
 Croscarmellose sodium
 Lactose monohydrate
 Magnesium stearate
 Povidone (K29/K32)
 Colloidal anhydrous silica
 Sodium lauryl sulphate
 Women
 Severe hepatic impairment (Child-Pugh C)

Elderly Patients
In a phase 3 trial of abiraterone, 71% of patients were 65 years and over and 28% were
75 years and over. No overall differences in safety or efficacy were observed between these
elderly patients and younger patients.

Pediatric Patients
Not applicable.

Renal Impairment
No dose adjustment is needed in renal impairment mild to moderate. However, there are
no data in patients with severe renal impairment, therefore it is recommended caution in these
patients.

Hepatic Impairment
The use of abiraterone should be cautiously assessed in patients with moderate hepatic
impairment, in whom the benefit clearly should outweigh the possible risk.
Abiraterone should not be used in patients with severe hepatic impairment.

Immunisations
Not applicable.

Warnings [2]

Mineralocorticoid Excess
Use with caution in patients with a history of cardiovascular disease. The safety of
abiraterone in patients with left ventricular ejection fraction (LVEF) <50% or NYHA Class
III or IV heart failure is not established.
Abiraterone: Abiraterone Acetate 5

Blood pressure should be under control and hypokalemia corrected before treatment.
Then, blood pressure, serum potassium and symptoms of fluid retention should be monitored
at least monthly.

Adrenocortical Insufficiency
Monitor for symptoms and signs of adrenocortical insufficiency. Increased dosage of
corticosteroids may be indicated before, during and after stressful situations.

Hepatotoxicity
Increases in liver enzymes have led to drug interruption, dose modification and/or
discontinuation. Monitor liver function and modify, interrupt, or discontinue abiraterone
dosing as recommended.

Food Effect
Abiraterone must be taken on an empty stomach. Exposure (area under the curve) of
abiraterone increases up to 10 fold when abiraterone acetate is taken with meals.

Toxicities [2]

System organ class Very common Common Uncommon Rare


(≥1/10) (≥1/100 to <1/10) (≥1/1000 to (≥1/10,000 and
<1/100) <1/1000)
Infections and infestations Sepsis
Urinary tract infection
Endocrine disorders Adrenal
insufficiency
Metabolism and nutrition Hypokalaemia Hypertriglyceridaemi
disorders a
Cardiac disorders Cardiac failure,
angina pectoris,
arrhythmia, atrial
fibrillation,
tachycardia
Vascular disorders Hypertension
Respiratory, thoracic and Allergic alveolitis
mediastinal disorders
Gastrointestinal disorders Diarrhoea Dyspepsia
Hepatobiliary disorders Increase levels of
AST and ALT
Skin and subcutaneous Rash
tissue disorders
Musculoskeletal and Myopathy,
connective tissue disorders rhabdomyolysis
Renal and urinary Haematuria
disorders
General disorders and Peripheral
administration site oedema
conditions
Injury, poisoning and Fractures
procedural complications
Unknown frequency
Myocardial infarction
6 A. Ballesteros

Dose Modifications [2]

 Dose adjustments for neutropenia and thrombocytopenia:


 None
 Dose adjustments for renal impairment
 None
 Dose adjustments for hepatic impairment:
 ALT or AST > 5 x upper normal limit (ULN): Interrupt treatment. Retreatment
may take place only after ALT returns to the patient‘s baseline, and at a reduced
dose level.
 If patients develop severe hepatotoxicity (ALT or AST 20 times or >20 ULN)
anytime while on therapy, treatment should be discontinued and patients should
not be re-treated.

Interactions [2]

Strong inducers of CYP3A4 has been proven to decrease the mean AUC of abiraterone
by approximately 50%. Therefore, these drugs such as phenytoin, carbamazepine, rifampicin,
St John‘s Worth, etc. are to be avoided, unless there is no therapeutic alternative.

CONCLUSION
Until recently, the only treatment that demonstrated improved survival in patients with
mCRPC was docetaxel-based chemotherapy. However, several pivotal phase 3 studies have
changed this scenario as three new agents have been added to the list of treatments after
demonstrating an improve survival. One of those agents is abiraterone.
Administration of abiraterone acetate may reduce the toxicity associated with a prolonged
taxane therapy and it could possibly delay emergence of taxane-resistant disease. Moreover,
patients who did not tolerate docetaxel well would be good candidates for abiraterone.

REFERENCES
[1] Mostaghel E. A., Marck B. T., Plymate S. R., Vessella R. L., Balk S., Matsumoto A.
M., Nelson P. S., Montgomery R. B. Resistance to CYP17A1 inhibition with
abiraterone in castration-resistant prostate cancer: induction of steroidogenesis and
androgen receptor splice variants. Clin Cancer Res. 2011 Sep 15; 17(18):5913-25.
[2] EMA, 2015. Abiraterone. Summary of Product Characteristics. pp. 1-9.
[3] EMC, Abiraterone SPC Imatinib SPC, 19/12/2014 from the eMC at 15:12 on 06/06/15.
John R. Horn, PharmD. FCCP, and Philip D. Hansten, PharmD: Get to Know an
Enzyme: CYP3A4. Pharmacy Times, online edition Sep 2008.
In: The Easy Book of Cancer Pharmacology ISBN: 978-1-63485-038-4
Editor: Esther Una Cidon © 2016 Nova Science Publishers, Inc.

Chapter 2

ALBUMIN-BOUND (NAB) PACLITAXEL, ABRAXANE®

V. Arrazubi, E. Galve and P. Martínez del Prado


Medical Oncology Department, Basurto University Hospital,
Bilbao, Spain

ABSTRACT
Albumin-bound (nab) paclitaxel is an albumin particle formulation of paclitaxel
which exploits the natural properties of albumin to enhance selective uptake and
accumulation of paclitaxel (an anti-microtubule agent) into tumors. This drug displays
linear pharmacokinetics over the clinically relevant dose range. After intravenous (iv)
infusion it is rapidly and extensively distributed and finally it is eliminated principally by
hepatic metabolism and biliary excretion. This drug is indicated for the treatment of
metastatic breast or pancreatic cancer patients. Nab-paclitaxel monotherapy is indicated
for breast cancer patients who have failed first-line treatment for metastatic disease and
for whom standard anthracycline containing therapy is not recommended. In patients with
adenocarcinoma of the pancreas the combination of nab-paclitaxel and gemcitabine
significantly prolonged overall survival and progression free survival versus gemcitabine
alone in the first-line setting. The most common clinically significant adverse reactions
associated to abraxane are neutropenia, peripheral neuropathy, arthralgia/myalgia and
gastrointestinal disorders. Nab-paclitaxel can be administered without the need for
special infusion sets or pre-medications. Administration of nab-paclitaxel in patients with
hepatic impairment should be performed with caution. Patients aged 75 and older should
be carefully assessed for their ability to tolerate nab-paclitaxel, especially in combination
with gemcitabine.

Keywords: abraxane, taxanes, nab-paclitaxel


varrazubi@gmail.com.
8 V. Arrazubi, E. Galve and P. Martínez del Prado

INTRODUCTION
Albumin-bound (nab) paclitaxel is an albumin particle formulation of paclitaxel which
exploits the natural properties of albumin to enhance selective uptake and accumulation of
paclitaxel (an anti-microtubule agent) into tumors. Nab-paclitaxel monotherapy is indicated
for breast cancer patients who have failed first-line treatment for metastatic disease and for
whom standard anthracycline containing therapy is not recommended.
In patients with adenocarcinoma of the pancreas the combination of nab-paclitaxel and
gemcitabine significantly prolonged overall survival and progression free survival versus
gemcitabine alone in the first-line setting. The most common side effects were neutropenia,
peripheral neuropathy, arthralgia/myalgia and gastrointestinal disorders. It is eliminated
principally by hepatic metabolism and biliary excretion, therefore administration in patients
with hepatic impairment should be performed with caution.

CLINICAL PHARMACOLOGY
Drug Classification

Antineoplastic agents, plant alkaloid and other natural products, taxanes [1].

MECHANISM OF ACTION
Albumin-bound (nab) paclitaxel is an albumin-bound nanoparticle formulation of
paclitaxel capable of utilizing the natural albumin pathways (endothelial transcytosis) to
selectively deliver larger amounts of drug into tumours; [2] also this drug leaves the
circulation passively via leaky vasculature surrounding the tumour.
This way paclitaxel is accumulated in tumour tissue. In addition, the albumin-bound
nanoparticles of paclitaxel overcome the solubility issues of paclitaxel and avoid the use of
synthetic solvents and the toxicities associated with their use [3, 4] Paclitaxel is an
antimicrotubule agent that promotes the assembly of microtubules from tubulin dimers and
stabilises microtubules by preventing depolymerisation. This stability results in the inhibition
of the normal dynamic reorganization of the microtubule network that is essential for vital
interphase and mitotic cellular functions. In addition, paclitaxel induces abnormal arrays or
―bundl es‖ of microtubules throughout the cell cycle and multiple asters of microtubules
during mitosis [1].

Pharmacokinetics

Pharmacokinetics of total paclitaxel following 30 and 180-minute infusions of nab-


paclitaxel at dose levels of 80 to 375 mg/m2 were determined in clinical studies [5, 6].
Albumin-Bound (NAB) Paclitaxel, Abraxane® 9

Absorption
Distribution Following iv administration of nab-paclitaxel, maximum concentrations
(Cmax) of paclitaxel were observed at the termination of infusion. Mean area
under the curve (AUC) increased linearly up to 300 mg/m2. In a repeat dose
study with patients receiving nab-paclitaxel administered IV at 260 mg/m2,
intrapatient variability in AUC was 19% (range 3.21%-27.7%). There was
no evidence for accumulation of paclitaxel with multiple treatment courses.
Nab-paclitaxel is evenly distributed into blood cells and plasma and is
highly bound to plasma proteins (94%). The mean apparent volume of
distribution (VZ) ranged from 236 to 772 l/m. This relatively large volume
exceeds the volume of total body water, indicating that nab-paclitaxel is
extensively distributed and bound to extravascular proteins and tissue [7].
Metabolism Nab-paclitaxel is metabolized primarily to 6α-hydroxypaclitaxel, and two
minor metabolites: 3´-p-hydroxypaclitaxel and 6-α-3´-p-
dihydroxypaclitaxel.
The formation of these hydroxylated metabolites is catalyzed by CYP2C8
and CYP3A4 liver enzymes [5, 6].
Elimination Paclitaxel as unchanged active substance and the different metabolites are
eliminated principally by hepatic metabolism and biliary excretion. Al the
clinical dose range of 80 to 300 mg/m2, the mean plasma clearance of
paclitaxel ranges from 13 to 30 l/h/m2, and the mean terminal half-life
ranges from 13 to 27 hours [5, 6].

Variable mean Nab-paclitaxel 260 mgr/m2 30 min


(coefficient of variation, %) infusion
CL (l/h/m2) 21.13 (43.8)
VZ (l/m2) 663.8 (48.1)
AUC∞ (ng/h/ml) 14,788.6 (45.3)
AUC∞da (ng/h/ml) 56.84 (46.3)
Cmax (ng/ml) 22,968.6 ()112.5
Cmaxda (ng/ml) 88.69 (114.2)
Tmax (hrs) 0.36 (45.2)
T1/2 (hrs) 21.6 (17.2)

CL, clearance; VZ, volume of distribution; AUC∞, area under the curve at
time infinity; AUC∞da, area under the curve at time infinity dose-adjusted;
Cmax, maximum concentration;, maximum concentration dose-adjusted; Tmax,
time to maximum concentration; T 1/2, elimination half-life.

INDICATIONS
Metastatic Breast Cancer

Nab-paclitaxel is indicated for the treatment of metastatic breast cancer in adult patients
who have failed first-line treatment for metastatic disease and for whom standard
anthracycline containing therapy is not indicated [8, 9].
10 V. Arrazubi, E. Galve and P. Martínez del Prado

Metastatic Pancreatic Adenocarcinoma

Nab-paclitaxel is also indicated in combination with gemcitabine for the first-line


treatment of adult patients with metastatic adenocarcinoma of the pancreas [10–13].

Dosages

For breast cancer the recommended dose of nab-paclitaxel is 260 mgr/m2 administered IV
over 30 minutes every 3 weeks [9].
For pancreatic adenocarcinoma the recommended dose of nab-paclitaxel in combination
with gemcitabine is 125 mgr/m2 administered IV over 30 minutes on days 1, 8 and 15 of each
28-day cycle. The concurrent recommended dose of gemcitabine is 1000 mgr/m in the same
schedule [10].

METHODS OF PREPARATION/ADMINISTRATION
Administer reconstituted nab-paclitaxel suspension iv using an infusion set incorporating
a 15 µm filter. After the administration, it is recommended to clean thoroughly with saline to
ensure all the drug has been administered.
Nab-paclitaxel can be administered without the need for special infusion sets or pre-
medications [5, 8, 9].
Limiting the infusion of this drug to 30 minutes, will reduce the likelihood of infusion-
related reactions.

SPECIAL INFORMATION AND CAUTIONS


Contraindications

 Hypersensitivity to the drug or the excipients listed below:


 Human albumin solution (containing sodium, sodium caprylate and N-acetyl
tryptophanate DL).
 Breast-feeding.
 Neutrophils <1500 ces/mm3

Elderly

For patients of 75 years and older receiving combination therapy of nab-paclitaxel and
gemcitabine there was a higher incidence of serious adverse reactions and adverse reactions
that led to treatment discontinuation including haematologic toxicities, peripheral neuropathy,
decreased appetite and dehydration [10].
Albumin-Bound (NAB) Paclitaxel, Abraxane® 11

Pediatric

Safety and effectiveness have not been evaluated.

Renal

There are insufficient data to permit dosage recommendations in patients with severe
renal (creatinine clearance <30 ml/min) or hepatic (bilirubin >5x ULN or AST > 10 x ULN)
impairment.

Hepatic

For monotherapy use 20% reduction in dose in recommended in patients with moderate
to severe hepatic impairment (total bilirubin > 1.5 to ≤ 5 x ULN and AST ≤10 x ULN). For
combination use there are insufficient data to permit dosage recommendations [5, 6].

Immunisations

Live vaccines should not be applied while taking the treatment or for at least 6 months
afterwards. Other vaccines can be administered, though may not give as much protection as
usual.
In any case, it is safe to be in contact with other people who have had live vaccines as
injections. There can be problems with oral vaccines. Any contacts with someone who has
had oral polio, cholera or typhoid vaccination recently, should be avoided.

Pregnancy

Paclitaxel has been shown to be clastogenic, teratogenic and fetotoxic and should not be
used in pregnancy. Men should be advised not to father a child while receiving treatment.

Breast-Feeding

It is not known if paclitaxel is excreted in human milk; however, it is recommended that


nursing should be discontinued during therapy.
12 V. Arrazubi, E. Galve and P. Martínez del Prado

TOXICITIES [9, 10]


Organic Very common Common Uncommon Rare (≥1/10,000
disorders (≥1/10) (>1/100 to <1/10) (≥1/1000 to <1/100) to <1/1000)
Infections Infection, urinary tract Oral candidiasis,
and infection, folliculitis, nasopharyngitis, cellulitis,
infestations upper respiratory tract herpes simplex, viral
infection, candidiasis, infection, pneumonia,
sinusitis, febrile catheter related infection,
neutropenia fungal infection, herpes
zoster, injection site
infection, sepsis,
neutropenic sepsis
Blood and Neutropenia, Hypokalaemia, decreased Hyposphosphataemia Pancitopenia
lymphatic anaemia, haematocrit, decreased red hypoalbuminaemia,
disorders leukopenia, blood cell count polydipsia, hyperglycaemia,
thrombo- hypocalcaemia,
cytopenia, hypoglycaemia,
lympho-penia, hiponatremia, increased
bone marrow blood lactate
suppression dehydrogenase, increased
blood creatinine, increased
blood glucose, increased
blood phosphorus,
decreased blood potassium,
increased bilirubin
Immuno-logical Hypersensitivity Severe
disorders hypersensitivity
Nutritional Dehydration, decreased
and metabolic appetite
disorders
Nervous Peripheral Insomnia, depression, Polyneuropathy, areflexia,
system disorders neuropathy, anxiety, peripheral sensory dyskinesia, hyporeflexia,
neuropathy, neurophaty, headache, neuralgia, sensory
hypo-aesthesia, dysgeusia, dizziness, loss, syncope, postural
paraesthesia peripheral motor dizziness, neuropathic pain,
neuropathy, ataxia, tremor,
sensory disturbance, restlessness
sommolence, oral
hypoaesthesia
Ocular disorders Increased lacrimation, Eye irritation, eye Cystoid
blurred vision, dry eye, pain, abnormal vision, macular
keratoconjunctivitis sicca, reduced visual acuity, oedema
madarosis conjunctivitis, visual
disturbance, eye
pruritus, keratitis
ENT disorders Rhinitis, rhinorrhea, verti Ear pain, tinnitus
Cardiac disorders Tachycardia, arrhythmia, Hypotension, Thrombosis,
supraventricular peripheral coldness, bradycardia,
tachycardia, hypertension, orthostatic hypotension cardiac arrest,
chest pain left ventricular
dysfunction,
congestive heart
failure,
atrioventricular
block
Vascular disorders
Respiratory and Interstitial pneumonitis, Productive cough, Radiation
thoracic dyspnea, epistaxis, exertional dyspnea, sinus pneumonitis
disorders pharyngolaryngeal pain, congestion, decreased
cough breath sounds, pleural
effusion, allergic rhinitis,
hoarseness,
Albumin-Bound (NAB) Paclitaxel, Abraxane® 13

Organic Very common Common Uncommon Rare


disorders (≥1/10) (>1/100 to <1/10) (≥1/1000 to <1/100) (≥1/10,000
to <1/1000)
nasal congestion, nasal
dryness, wheezing,
pulmonary emboli,
pulmonary thromboembolism
Gastro-intestinal Nausea, Abdominal pain, Dysphagia, flatulence,
disorders diarrhea, abdominal distension, glossodynia, dry mouth,
vomiting, upper abdominal pain, gingival pain, loose stools,
constipation, dyspepsia, oesophagitis, lower
stomatitis, gastrooesophageal abdominal pain, mouth
anorexia reflux disease ulceration, oral pain, rectal
haemorrhage, hepatomegaly
Hepatobiliary Increased alanine
disorders aminotransferase,
increased aspartate
aminotransferase,
increased gamma-
glutamyltransferase,
increased blood alkaline
phosphatase
Skin and hair Alopecia, rash Nail disorder, pruritus, Nail bed tenderness, Radiation recall
disorders dry skin, erythema, nail urticarial, skin pain, phenomenon
pigmentation/ photosensitivity reaction, extra-vasation
discolouration, skin pigmentation disorder,
hyperpigmentation, pruritic rash, skin disorder,
onycholysis, nail changes hyperhidrosis,
onychomadesis,
erythematous rash,
generalized rash, dermatitis,
night sweats, maculo-papular
rash, vitiligo, hypotrichosis,
nail iscomfort, generalized
pruritus, macular rash,
papular rash, skin lesion,
swollen face
Musculo-skeletal Arthralgia, Pain in extremity, bone Contusion, chest wall pain,
disorders myalgia pain, back pain, muscle muscular weakness, neck
cramps, limb pain pain, groin pain, muscle
spasms, musculoskeletal
pain, flank pain, limb
discomfort, muscle weakness
General Fatigue, Increased body Breast pain, chest discomfort,
disorders asthenia, temperature, decreased abdominal gait, swelling,
pyrexia weigh, flushing, hot injection site reaction, fluid
flushes, lymphedema, retention, hypersensitivity,
peripheral oedema, metastatic pain, tumour
mucosal inflammation, necrosis, increased weight
pain, rigors, oedema,
weakness, decreased
performance status,
influenza-like illness,
malaise, lethargy,
hyperpyrexia
Renal disorders Dysuria, polakiuria,
haematuria, nocturia,
polyuria, urinary
incontinence
Very rare (<1/10,000)
Steven Johnson‘s syndrome
14 V. Arrazubi, E. Galve and P. Martínez del Prado

In combination with gemcitabine:

Organic disorders Very common Common Uncommon


(≥1/10) (>1/100 to <1/10) (≥1/1000 to <1/100)
Infections and Sepsis, pneumonia,
infestations oral candidiasis
Blood and lymphatic Neutropenia, anaemia, Pancitopenia, aspartate
disorders thrombocytopenia, aminotransferase increased,
hypokalaemia, alanine blood bilirubin increased,
aminotransferase increased blood creatinine increased
Immunological Infusion site reaction
disorders
Nervous system Peripheral neuropathy, Anxiety VII nerve paralysis
disorders dysgeusia, headache,
dizziness, insomnia,
depression
Ocular disorders Lacrimation increase Cystoid macular
oedema
ENT disorders Dry throat, nasal
dryness
Cardiac disorders Cardiac failure congestive,
tachycardia, hypotension,
hypertension
Respiratory and Dyspnea, epistaxis, cough Pneumonitis, nasal congestion
thoracic disorders
Gastrointestinal Nausea, diarrhoea, Stomatitis, intestinal
disorders vomiting, constipation, obstruction, colitis, dry mouth,
abdominal pain upper cholangitis
Skin and hair Alopecia, rash Pruritus, dry skin, nail
disorders disorder, flushing
Musculoskeletal Pain in extremity, Muscular weakness, bone pain
disorders arthralgia, myalgia
General disorders Dehydration, decreased Haemolytic uraemic
appetite, weigh decreased, syndrome,
Fatigue, oedema peripheral, thrombotic
pyrexia, asthenia, chills thrombocytopenic
purpura
Renal disorders Acute renal failure

Dose Modifications

Pancreatic adenocarcinoma (10)


Dose adjustments during treatment

Dose Level Abraxane Dose Gemcitabine Dose (mg/m2)


(mg/m2)
Full dose 125 1000
1st dose level reduction 100 800
2nd dose level reduction 75 600
If additional dose reduction Discontinue treatment Discontinue treatment
required
Albumin-Bound (NAB) Paclitaxel, Abraxane® 15

Dose modifications for neutropenia and/or thrombocytopenia at the start of a cycle or


within a cycle

Cycle Day ANC count Platelet count Abraxane Gemcitabine


(cells/mm3) (cells/mm3) Dose Dose
Day 1 <1500 OR <100,000 Delay doses until recovery
Day 8 ≥500 but OR ≥50,000 but Reduce doses 1 dose level
<1000 <75,000
<500 OR <50,000 Withhold doses
Day 15: If Day 8 doses were given without modification:
Day 15 ≥500 but OR ≥50,000 Treat with Day 8 dose level and follow with WBC
<1000 but <75,000 Growth Factors
OR Reduce doses 1 dose level from
Day 8 doses
<500 OR <50,000 Withhold doses
Day 15: If Day 8 doses were reduced:
Day 15 ≥1000 AND ≥75,000 Return to the Day 1 dose levels and follow with
WBC Growth Factors
OR Treat with same doses as Day 8
≥500 but OR ≥50,000 but Treat with Day 8 dose levels and follow with
<1000 <75,000 WBC Growth Factors
OR Reduce doses 1 dose level from Day 8 doses
<500 OR <50,000 Withhold doses
Day 15: If day 8 doses were withheld:
Day 15 ≥1000 AND ≥75,000 Return to Day 1 dose levels and follow with WBC
Growth Factors
OR Reduce doses 1 dose level from Day 1 doses
≥500 but OR ≥50,000 but Reduce 1 dose level and follow with WBC
<1000 <75,000 Growth Factors
OR Reduce doses 2 dose levels from Day 1 doses
<500 OR <0,000 Withhold doses
Abbreviations: ANC = Absolute Neutrophil Count; WBC = white blood cell.

Dose modifications for other adverse drug reactions in patients with pancreatic
adenocarcinoma

Adverse Drug Reaction (ADR) Abraxane Dose Gemcitabine Dose


Febrile Neutropenia: Withhold doses until fever resolves and ANC ≥ 1500; resume at next
Grade 3 or 4 lower dose levela
Peripheral Neuropathy: Withhold dose until improves Treat with same dose
Grade 3 or 4 to ≤ Grade 1;
resume at next lower dose levela
Cutaneous Toxicity: Reduce to next lower dose levela;
Grade 2 or 3 discontinue treatment if ADR persists
Gastrointestinal Toxicity: Withhold doses until improves to ≤ Grade 1;
Grade 3 mucositis or diarrhoea resume at next lower dose levela

Breast cancer (9)


Dose adjustments during treatment.
Adverse event (AE) Toxicity occurrence Dose recomendations
Starting dose: 260 mgr/m2
Severe neutropenia (neutrophil 1ª 220 mgr/m2 q3w
count <500 cells/mm3 for a week 2ª 180 mgr/m2 q3w
or longer) or severe sensory
neuropathy
16 V. Arrazubi, E. Galve and P. Martínez del Prado

INTERACTIONS
Caution should be exercised when administering paclitaxel concomitantly with medicines
known to inhibit (e.g., imidazole antifungals, fluoxetine or cimetide) or induce (e.g.,
carbamazepine of phenytoin) either CYP2C8 or CYP3A4 isoenzymes o cytochrome P450.

CONCLUSION
Nab-paclitaxel has been developed with an interesting rational that permits not only
overcome the solubility issues of paclitaxel and avoid the use of synthetic solvents and the
toxicities associated with their use, but also enhance selective uptake and accumulation of
paclitaxel into tumors. This drug has been tested in phase III trials and has demonstrated a
survival benefit in patients with breast or pancreatic metastatic cancer with manageable
toxicity.

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pharmacokinetics trial of ABI-007, a novel nanoparticle formulation of paclitaxel in
patients with advanced nonhematologic malignancies. J Clin Oncol [Internet]. 2005
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Cremophor EL-mediated alteration of paclitaxel distribution in human blood: clinical
pharmacokinetic implications. Cancer Res [Internet]. 1999 Apr 1 [cited 2015 Nov
29];59(7):1454–7. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10197613.
[8] Ibrahim NK, Samuels B, Page R, Doval D, Patel KM, Rao SC, et al. Multicenter phase
II trial of ABI-007, an albumin-bound paclitaxel, in women with metastatic breast
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In: The Easy Book of Cancer Pharmacology ISBN: 978-1-63485-038-4
Editor: Esther Una Cidon © 2016 Nova Science Publishers, Inc.

Chapter 3

AFLIBERCEPT. ZALTRAP®

M. López-Gómez*, B. García de Santiago, E. Jiménez,


A. M. Jiménez-Gordo and E. Casado
Medical Oncology Department,
University Hospital ―I
nfanta Sofia‖,
Madrid, Spain

ABSTRACT
Angiogenesis is a very complex mechanism controlled by several vascular
endothelial growth factors (VEGF) such as VEGF-A and VEGF-B and placental growth
factors (PlGF) [1, 2]. VEGF-A ligands to VEGFR-1 and VEGFR-2, two receptors located
in endothelial cells surface, whereas VEGF-B and PlGF ligand only to VEGFR-1
receptor. Increase receptor stimuli results in a pathological vascularization and increased
vessel permeability.
Ziv-aflibercept (also known as VEGF-trap) is an inhibitor of the VEGF which
prevents VEGF binding/activation to their receptors leading to antiangiogenesis and
tumor regression, and has shown promising results in colon cancer; currently, it is
approved for use in combination with FOLFIRI for the treatment of patients with
metastatic colorectal cancer (mCRC) that is resistant to or has progressed following an
oxaliplatin-containing regimen. his approval is based on results from the placebo-
controlled VELOUR trial, in which 1226 patients with oxaliplatin-refractory mCRC were
randomly assigned to aflibercept (4 mg/kg IV) or placebo, plus FOLFIRI, every two
weeks until progression.
Median overall survival was significantly longer in patients treated with aflibercept
(13.5 versus 12.1 months) [3]. In this trial, benefit and safety were similar regardless of
prior bevacizumab exposure.
The side-effect profile of aflibercept plus FOLFIRI in the VELOUR trial was
consistent with other agents targeting VEGF (bleeding, hypertension, proteinuria, wound
infection and arterial thromboembolic events). However, the rate of diarrhea, mucositis,
complicated neutropenia, infection, and fatigue associated with aflibercept in this trial are
higher than bevacizumab-related. One of the main precautions to be considered with the
use of Aflibercept is that it is advisable to stop treatment at least 28 days (preferable six

*
E-mail: miriam.lopez@movistar.es.
20 M. López-Gómez, B. García de Santiago, E. Jiménez et al.

to eight weeks) prior to mayor surgery (excluding emergency situations) because of the
risk of impaired wound healing.

Keywords: aflibercept, antiangiogenic agents, angiogenesis

INTRODUCTION
Ziv-aflibercept, a recombinant fusion that consists of VEGF-binding portions from the
extracellular domains of human VEGF receptors 1 and 2 fused to the Fc portion of the human
IgG1 immunoglobulin, was approved by the Food and Drug Administration (FDA) in August
2012 for use in combination with 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) for the
treatment of patients with mCRC that is resistant to or has progressed following treatment
with an oxaliplatin-containing regimen.
This approval is based on results from the VELOUR trial which achieved a significantly
longer overall survival in patients treated with aflibercept compared to placebo (13.5 versus
12.1 months) [3]. Sometimes fatal hemorrhage, including gastrointestinal (GI), has been
reported, thus it is necessary to monitor patients for signs and symptoms of GI and other
severe bleeding. Aflibercept should be discontinued if GI perforation occurs and as it causes
severe compromised would healing, it needs to be stopped for at least 4 weeks prior to
elective surgery and do not resume it for at least 4 weeks after major surgery and until the
surgical wound is fully healed.

CLINICAL PHARMACOLOGY
Drug Classification

Aflibercept is an inhibitor of the VEGF.

MECHANISM OF ACTION
VEGF-trap/ziv-aflibercept is a recombinant fusion protein which is comprised of portions
of binding domains for vascular endothelial growth factor (VEGF) receptors 1 and 2, attached
to the Fc portion of human IgG1 [4].
Ziv-aflibercept acts as a decoy receptor for VEGF-A, VEGF-B, and placental growth
factor (PlGF) which prevents VEGF receptor binding/activation to their receptors (an action
critical to angiogenesis). As a result of this action, inhibition of angiogenesis and tumor
regression occurs.

MECHANISM OF RESISTANCE
Not applicable.
Aflibercept. Zaltrap® 21

PHARMACOKINETICS [6]
Absorption 4 mgr/kgr intravenously every two weeks
(excess of free ablibercept compared to VEGF-bound)
Distribution 8 liters volume
Metabolism Not applicable (as a protein it should end up in aminoacides)
Excretion Binds to endogenous VEGF-A to form an inactive complex. At
higher than 2mg/Kg clearance was 1.0 l/daily and half-life
elimination: ~6 days (range: 4 to 7 days)
Minimal renal clearance.
Other mechanisms: protein catabolism

INDICATIONS
Aflibercept in combination with FOLFIRI regimen (Irinotecan/5- Fluorouracil/Folinic
Acid) is indicated for patients with mCRC that is resistant or has progressed following an
oxaliplatin—containing regimen [6, 7].

DOSAGES
Aflibercept recommended dose is 4 mg per kg every two weeks. Treatment should be
continued until disease progression or unacceptable toxicity.

METHODS OF PREPARATION/ADMINISTRATION [6]


Aflibercept is available as:

 100 mg per 4 mL (25 mg per ml) solution, single-use vial


 200 mg per 8 mL (25 mg per ml) solution, single-use vial

Aflibercept should be administered as an intravenous infusion over 1 hour and prior to


any component of the FOLFIRI regimen on the day of treatment. FOLFIRI doses should be
irinotecan 180 mgr/m2 diluted in 500 ml of 5% dextrose in water administered over 90
minutes, leucovorin 400 mgr/m2 diluted in 250 ml of 5% dextrose water administered over 2
hours, fluorouracil 400 mgr/m2 administered as a push over 5 minutes followed by
fluorouracil 2400 mgr/m2 diluted in 500 to 1000 ml of 5% dextrose water and administered
over 46 hours.
Aflibercept must never be administered as an intravenous push or bolus as high
osmolarity (1000mOsmol/Kg) and it never must be combined with other drugs in the same
infusion bag or intravenous line.
22 M. López-Gómez, B. García de Santiago, E. Jiménez et al.

SPECIAL INFORMATION AND CAUTIONS [6]


Contraindications

- Hipersensitivity to aflibercept or to one of the excipients listed below:

 Saccharose
 Sodium chloride
 Sodium citrate dihydrate
 Citric acid monohydrate
 Polysorbate 20
 Dibasic sodium phosphate heptahydrate
 Monobasic sodium phosphate monohydrate
 Sodium hydroxide and/or hydrochloric acid (to adjust pH)
 Water for injections

- Ophthalmic/intravitreal use, due to hyperosmotic properties

Elderly Patients

No adjustment in dose is necessary for elderly patients.

Pediatric Patients

There is not a specific recommendation for this population.

Renal Impairment

No adjustment in dose is needed in patients with mild to moderate renal impairment.


However, data are limited in patients with severe renal impairment, therefore these
patients should be treated cautiously.

Hepatic Impairment

No adjustment in dose is needed in patients with mild to moderate hepatic impairment.


There are no data in patients with severe hepatic insufficiency.
Aflibercept. Zaltrap® 23

WARNINGS [6]
Hemorrhage

Patients treated with Aflibercept have an increased risk of hemorrhage, including GI


hemorrhage, hematuria, and post-procedural hemorrhage. Severe and sometimes fatal
hemorrhagic events such as intracranial hemorrhage and pulmonary hemorrhage/hemoptysis
have also been reported.
It is important to monitor patients for signs and symptoms of bleeding in order to
discontinue Aflibercept administration and it must never be initiated in patients that present
severe hemorrhage.

Gastrointestinal Perforation

Patients must be monitored for signs and symptoms of GI perforation during treatment
with Aflibercept and discontinue it in those patients who experience perforation.

Compromised Wound Healing

Aflibercept impairs wound healing.


Therefore, it must be suspended for at least 4 weeks prior to elective surgery and it
should not be resumed for at least 4 weeks following major surgery and until the surgical
wound is fully healed. For minor surgery, such as central venous access port placement,
biopsy, and tooth extraction, Aflibercept may be initiated/resumed once the surgical wound is
fully healed.

Fistula Formation

It can involve GI and non-GI sites (anal, enterovesical, enterocutaneous, colovaginal,


intestinal sites).
Aflibercept therapy must be discontinued in patients who develop fistula.

Hypertension

Blood pressure must be monitored every two weeks or more frequently during treatment
with aflibercept.
Appropriate anti-hypertensive therapy must be initiated and aflibercept must be
temporarily suspended in patients with uncontrolled hypertension.
Once the blood pressure is controlled Aflibercept must be permanently reduced to 2 mg
per kg for subsequent cycles and permanently discontinued in patients with hypertensive
crisis or hypertensive encephalopathy.
24 M. López-Gómez, B. García de Santiago, E. Jiménez et al.

Arterial Thromboembolic Events

These include transient ischemic attack, cerebrovascular accident, and angina pectoris. In
these cases, Aflibercept must be discontinued.

Proteinuria

Proteinuria must be monitored by urine dipstick analysis and urinary protein creatinine
ratio (UPCR).
Nephrotic syndrome and thrombotic microangiopathy must also be monitored during
treatment. See below for dose reductions.

Neutropenic Complications

Neutropenic complications (Febrile neutropenia and neutropenic infection) can be seen in


patients under therapy with aflibercept. Blood test must be monitored prior to initiation of
each cycle of aflibercept and its administration must be delayed until neutrophil count is at or
above 1.5 x 109/l.

Diarrhea and Dehydration

The incidence of diarrhea is increased in patients who are age 65 years or older as
compared to patients younger than 65 years of age, therefore elderly patients should be
closely monitored for diarrhea.

Pregnancy and Nursing

There is a potential risk to the fetus or neonate. Highly effective contraception measures
must be recommended in both males and females during and for at least 3 months following
last dose of aflibercept therapy.

Immunisations

Live vaccines should not be applied while taking the treatment or for at least 6 months
afterwards. Other vaccines can be administered, though may not give as much protection as
usual.
In any case, it is safe to be in contact with other people who have had live vaccines as
injections.
There can be problems with oral vaccines. Any contacts with someone who has had oral
polio, cholera or typhoid vaccination recently, should be avoided.
Aflibercept. Zaltrap® 25

TOXICITIES
System organ Very common Common Uncommon Rare
class (≥ 1/10) (≥ 1/100 to < 1/10) (≥ 1/1000 to < (≥1/10,000
1/100) and
<1/1000)

Vascular Hypertension, Venous Thrombotic


disorders Bleeding, thromboembolic microangiopathy,
Epistaxis events, grade 3-4 GI
arterial hemorrhagia
thromboembolic
events,
pulmonary embolism
Skin and Palmar-plantar Hyperpigmentation Wound healing
subcutaneous erythrodysesthesia impaired
tissue disorders
Infections and Infection Urinary tract infection,
infestation neutropenic fever,
disorders neutropenic
infection/sepsis

Metabolism and Weight loss


nutrition disorders
Nervous system Headache Reversible posterior
disorders encephalopathy
syndrome (RPLS)
Cardiac disorders
Gastrointestinal Diarrhea, stomatitis, Hemorrhoids, GI perforation
disorders anorexia, abdominal proctalgia,
pain rectal hemorrhage,
GI perforation
Hepatobiliary AST increased, ALT
disorders increased
Respiratory, Dyspnea, dysphonia Oropharyngeal pain,
thoracic and rhinorrhea
mediastinal
disorders
Renal and urinary Nephrotic
disorders syndrome

General disorders Weakness, fatigue Fistula formation, Hypersensitivity


and Dehydration,
administration Antibody formation
site conditions
investigations Leukopenia,
neutropenia,
thrombocytopenia,
AST increased, ALT
increased,
creatinine increased,
proteinuria
26 M. López-Gómez, B. García de Santiago, E. Jiménez et al.

DOSE MODIFICATIONS
1. Aflibercept must be discontinued for:

- Severe haemorrhage.
- GI perforation.
- Compromise wound healing.
- Fistula formation.
- Hypertensive crisis or hypertensive encephalopathy.
- Arterial thromboembolic events.
- Nephrotic syndrome or thrombotic microangiopathy.
- Reversible posterior leukoencephalopathy syndrome.

2. Aflibercept must be temporarily suspended for:

- Elective surgery (at least 4 weeks prior to the date of surgery).


- Recurrent or severe hypertension, until controlled. Upon resumption, Aflibercept
dose must be permanently reduced to 2 mg per kg.
- Proteinuria of 2 grams per 24 hours:
- It should be resumed when proteinuria is less than 2 grams per 24 hours.
- For recurrent proteinuria, aflibercept should be suspended until proteinuria is
less than 2 grams per 24 hours and then permanently reduced

INTERACTIONS
Attention must be paid when combining aflibercept with the following drugs:

- Biphosphonate derivatives: angiogenesis inhibitors may enhance the adverse/toxic


effect of bisphosphonate derivatives, specifically, the risk for osteonecrosis of the
jaw.
- Clozapine, an atypical antipsychotic drug. Aflibercept may enhance the adverse/toxic
effect of clozapine and increase the risk for agranulocytosis.

CONCLUSION
Ziv-aflibercept is a recombinant protein that has part of the human VEGF receptors 1 and
2 fused to the Fc portion of human IgG1. It is designed to function as a VEGF trap to prevent
activation of VEGF receptors and thus inhibit angiogenesis. Ziv-aflibercept activity has been
tested in the VELOUR trial in second line therapy in patients with a diagnosis of mCRC that
has progressed after one regimen containing oxaliplatin. Aflibercept increases median overall
survival in this setting compared to placebo. It has only shown activity when giving in
conjunction with FOLFIRI in FOLFIRI naïve patients, and there are no data of activity of
Aflibercept. Zaltrap® 27

aflibercept in monotherapy. The benefits of this combination are maintained also in those
patients who had received bevacizumab in first line setting [7].
As a result of this, the NCCN guidelines recommend ziv-aflibercept in combination with
FOLFIRI or irinotecan in patients progressing a previous regimen not containing irinotecan
[8]. The most frequent adverse events related to aflibercept are asthenia/fatigue, infections,
diarrhea, hypertension and venous thromboembolic events.

REFERENCES
[1] Carmeliet P., Jain R. K. Molecular mechanisms and clinical applications of
angiogenesis. Nature, 2011; 473 (7347): 298-307. doi: 10.1038/nature10144.
[2] Augustin H. G. Tubes, branches and pillars: the many ways of forming a new
vasculature. Circ. Res., 2001; 89(8):645-7.
[3] Van Cutsem E., Tabernero J., Lakomy R., Prenen H., Prausová J., Macarulla T., et al.
Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a
phase III randomized trial in patients with metastatic colorectal cancer previously
treated with an oxaliplatin-based regimen. J. Clin. Oncol., 2012; 30(28):3499.
[4] http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm314438.htm.
[5] EMA, 2014. Aflibercept. Summary of Product Characteristics. Pp.: 1-44.
[6] Tabernero J., Van Cutsem E., Lakomy R., Prausova J., Ruff P., Van Hazel G. A. et al.
Aflibercept versus placebo in combination with fluorouracil, leucovorin and irinotecan
in the treatment of previously treated metastatic colorectal cancer: prespecified
subgroup analyses from the VELOUR trial. Eur. J. Cancer, 2014, 50(2):320-31.
[7] NCCN guidelines. Colon cancer, version 2.2015.
In: The Easy Book of Cancer Pharmacology ISBN: 978-1-63485-038-4
Editor: Esther Una Cidon © 2016 Nova Science Publishers, Inc.

Chapter 4

AXITINIB. INLYTA®

A. Ballesteros
Directorate Pharmacist, Oncology, Poole Hospital Foundation Trust

ABSTRACT
Axitinib is a type-1 kinase inhibitor which inhibits several receptor tyrosine kinases
including vascular endothelial growth factor receptor (VEGFR) 1, 2 and 3, platelet
derived growth factor receptor (PDGFR), and cKIT. At present its main indication are the
treatment of adult patients with advanced renal cell carcinoma (RCC) after failure of
prior treatment with a Tyrosine Kinase Inhibitor (TKI) or a cytokine [1-3].

Keywords: axitinib, tyrosine kinases, renal cell carcinoma

INTRODUCTION
Axitinib is a potent and selective inhibitor of VEGF receptor tyrosine kinases 1, 2, and 3.
It is an oral small-molecule tyrosine kinase inhibitor targeted to angiogenesis. Axitinib is
indicated in advanced RCC.
Pharmacokinetic studies show that axitinib is rapidly absorbed, reaching peak
concentrations within 2-6 hours. The dose is 5 mg twice daily orally and this is metabolized
primarily in the liver via the cytochrome P450 (CYP) system with less than 1% of the
administered drug passing unchanged in the urine. Common side effects include
hypertension, fatigue and dysphonia [2, 3].


Email: entoatucass@googlemail.com.
30 A. Ballesteros

CLINICAL PHARMACOLOGY
Drug Classification

Antineoplastic agents, protein kinase inhibitors [1].

Mechanism of Action

Axitinib is a potent and selective tyrosine kinase inhibitor of VEGFR-1, VEGFR-2 and
VEGFR-3.
These receptors are implicated in pathologic angiogenesis, tumour growth, and metastatic
progression of cancer. Axitinib has been shown to potently inhibit VEGF-mediated
endothelial cell proliferation and survival. Axitinib inhibited the phosphorylation of VEGFR-
2 in xenograft tumour vasculature that expressed the target In Vivo and produced tumour
growth delay, regression, and inhibition of metastases in many experimental models of cancer
[2, 3].

Pharmacokinetics [2, 3]

Absorption Mean absolute bioavailability is 58% compared to intravenous administration. The


plasma half-life of axitinib ranges from 2.5 to 6.1 hours. Dosing of axitinib at 5
mg twice daily resulted in less than two-fold accumulation compared to
administration of a single dose. Based on the short half-life of axitinib, steady
state is expected within 2 to 3 days of the initial dose.
Peak axitinib concentrations in plasma are generally reached within 4 hours
following oral administration of axitinib with median Tmax ranging from 2.5 to
4.1 hours. Administration of axitinib with a moderate fat meal resulted in 10%
lower exposure compared to overnight fasting. A high fat, high-calorie meal
resulted in 19% higher exposure compared to overnight fasting. Axitinib may be
administered with or without food.
Distribution The average Cmax and AUC increased proportionally over an axitinib dosing
range of 5 to 10 mg. In Vitro binding of axitinib to human plasma proteins is >
99% with preferential binding to albumin and moderate binding to α1-acid
glycoprotein. At the 5 mg twice daily dose in the fed state, the geometric mean
peak plasma concentration and 24-hour AUC were 27.8 ng/mL and 265 ng.h/mL,
respectively, in patients with advanced RCC. The geometric mean oral clearance
and apparent volume of distribution were 38 L/h and 160 L, respectively
Metabolism Axitinib is metabolised primarily in the liver by CYP3A4/5 and to a lesser extent
by CYP1A2, CYP2C19, and UGT1A1.
The plasma half-life of axitinib ranges from 2.5 to 6.1 hours. Dosing of axitinib at
5 mg twice daily resulted in less than two-fold accumulation compared to
administration of a single dose. Based on the short half-life of axitinib, steady
state is expected within 2 to 3 days of the initial dose.
Excretion Faeces (60%), urine (23%)
Axitinib. Inlyta® 31

Mechanism of Resistance [3]

Mechanisms of resistance to antiangiogenic therapy include amplification of


proangiogenic genes, secretion of multiple proangiogenic factors (e.g., angiopoietin,
VEGF(R) and ephrins), recruitment of proangiogenic bone marrow– derived cells, and escape
mechanisms via different modes of vascularization. The first three mechanisms ultimately
result in greater levels of VEGF. Higher VEGF and VEGFR levels might lead to specific
angiogenic inhibitor–related toxicities and faster regrowth of the tumor vasculature when the
anti-VEGF drug is discontinued.

Indications

Adult patient with advanced RCC after failure to prior treatment with sunitinib and
cytokines [1].

Dosage

5 mg twice daily orally, with/without food. Tablets should be swallowed full with a glass
of water [1].

Methods of Preparation/Administration [1]

Oral route.
Axitinib is available in different concentrations, 1 mg, 3 mg, 5 mg and 7 mg tablets.

Special Information and Cautions [1]

Contraindications
Hypersensitivity to axitinib or one of the excipients which are listed below:

-Tablet core:
microcrystalline cellulose
lactose monohydrate
Croscarmellose sodium
Magnesium stearate
-Tablet coating:
hypromellose
Titanium dioxide (E171)
lactose monohydrate
Triacetin (E1518)
Red iron oxide (E172)
32 A. Ballesteros

Elderly
Patients ≥ 65 years do not require dose adjustments.

Pediatric
It is not established safety or efficacy of axitinib in children or teenagers below 18 years
old.

Renal Impairment
No dose adjustment is required. Virtually no data are available regarding axitinib
treatment in patients with a creatinine clearance of < 15 mL/min.

Hepatic Impairment
No dose adjustment is required when administering axitinib to patients with mild hepatic
impairment (Child-Pugh class A). A dose decrease is recommended when administering
axitinib to patients with moderate hepatic impairment (Child-Pugh class B) (e.g., the starting
dose should be reduced from 5 mg twice daily to 2 mg twice daily). Axitinib has not been
studied in patients with severe hepatic impairment (Child-Pugh class C) and should not be
used in this population.

Breast-Feeding
It is unknown if axitinib is excreted into human milk. Its use is not recommended in this
population.

Pregnancy
Women of childbearing potential should be advised to avoid becoming pregnant during
therapy and for up to 4 weeks following therapy. Male and female patients should be using
effective contraception methods during treatment.

Immunisations
Live vaccines should not be applied while taking the treatment or for at least 6 months
afterwards. Other vaccines can be administered, though may not give as much protection as
usual. In any case, it is safe to be in contact with other people who have had live vaccines as
injections. There can be problems with oral vaccines. Any contacts with someone who has
had oral polio, cholera or typhoid vaccination recently, should be avoided.

Warnings [1]

Hypertension
Hypertension including hypertensive crisis has been observed.
Blood pressure should be well-controlled prior to starting axitinib and monitoring and/or
further treatment is necessary.
If persistent hypertension despite use of anti-hypertensive medications, axitinib should be
reduced.
Axitinib. Inlyta® 33

Thromboembolic Events
Arterial and venous thrombotic events have been observed and can be fatal. Axitinib
should be used with caution in patients who are at increased risk for these events.

Hemorrhagic Events
Including fatal events.
Axitinib has not been studied in patients with untreated brain metastasis or recent active
gastrointestinal bleeding and should not be used in those patients.

Toxicities [1]

System organ class Very common Common Uncommon


(≥ 1/10) (≥ 1/100 to < 1/10) (≥ 1/1000 to <
1/100)
Tinnitus Vascular Hypertension, Venous/arterial
disorders haemorrhage thromboembolism
Skin, hair and Erythrodysesthesia Itchiness, erythema, alopecia
subcutaneous tissue palmoplantar, ezcema,
disorders dryness
ENT disorders
Musculoskeletal Arthralgia, painful Myalgia
disorders limbs
Metabolism and
nutrition disorders
Nervous system Headache Dizziness Posterior
disorders reversible
encephalopathy
Cardiac disorders Cardiac insufficiency
Gastrointestinal Diarrhoea, nausea, Oropharyngeal pain,
disorders vomiting, abdominal flatulence, upper abdominal
pain, constipation, pain, haemorrhoids, fistulae,
stomatitis, dyspepsia gastrointestinal perforation,
glossodynia
Hepatobiliary Hyperbilirubinemia
disorders
Respiratory, thoracic Dyspnea, cough,
and mediastinal dysphonia
disorders
Endocrine disorders Hypothyroidism Hyperthyroidism
Renal and urinary Proteinuria Renal failure
disorders
General disorders and Anorexia, dysgeusia, Dehydration
administration site fatigue, mucositis,
conditions weight loss
Investigations Hyperkalemia,
hypercalcemia, increase in
lipase, ALT, amylase, AST,
alkaline phosphatase,
creatinine, TSH
Blood and lymphatic Anaemia, thrombocytopenia, Neutropenia,
disorders policytemia leucopenia
34 A. Ballesteros

Dose Modifications [1]

Hepatic Impairment
No dose adjustment is required when administering axitinib to patients with mild hepatic
impairment (Child-Pugh class A). A dose decrease is recommended when administering
axitinib to patients with moderate hepatic impairment (Child-Pugh class B) (e.g., the starting
dose should be reduced from 5 mg twice daily to 2 mg twice daily). Axitinib has not been
studied in patients with severe hepatic impairment (Child-Pugh class C) and should not be
used in this population

Concomitant Strong CYP3A4/5 Inhibitors


Co-administration of axitinib with strong CYP3A4/5 inhibitors may increase axitinib
plasma concentrations. Selection of an alternate concomitant medicinal product with no or
minimal CYP3A4/5 inhibition potential is recommended. Although axitinib dose adjustment
has not been studied in patients receiving strong CYP3A4/5 inhibitors, if a strong CYP3A4/5
inhibitor must be co-administered, a dose decrease of axitinib to approximately half the dose
(e.g., the starting dose should be reduced from 5 mg twice daily to 2 mg twice daily) is
recommended.

Concomitant Strong CYP3A4/5 Inducers


Co-administration of axitinib with strong CYP3A4/5 inducers may decrease axitinib
plasma concentrations. Selection of an alternate concomitant medicinal product with no or
minimal CYP3A4/5 induction potential is recommended. Although axitinib dose adjustment
has not been studied in patients receiving strong CYP3A4/5 inducers, if a strong CYP3A4/5
inducer must be co-administered, a gradual dose increase of axitinib is recommended.

Interactions [1]

CYP3A4/5 Inhibitors
Ketoconazole, a strong inhibitor of CYP3A4/5, administered at a dose of 400 mg once
daily for 7 days, increased the mean area under the curve (AUC) 2-fold and Cmax 1.5-fold of
a single 5-mg oral dose of axitinib in healthy volunteers. Co-administration of axitinib with
strong CYP3A4/5 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, erythromycin,
atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin) may
increase axitinib plasma concentrations. Grapefruit may also increase axitinib plasma
concentrations. Selection of concomitant medicinal products with no or minimal CYP3A4/5
inhibition potential is recommended. If a strong CYP3A4/5 inhibitor must be co-
administered, a dose adjustment of axitinib is recommended.

CYP1A2 and CYP2C19 Inhibitors


CYP1A2 and CYP2C19 constitute minor (< 10%) pathways in axitinib metabolism. The
effect of strong inhibitors of these isozymes on axitinib pharmacokinetics has not been
studied. Caution should be exercised due to the risk of increased axitinib plasma
concentrations in patients taking strong inhibitors of these isozymes.
Axitinib. Inlyta® 35

CYP3A4/5 Inducers
Rifampicin, a strong inducer of CYP3A4/5, administered at a dose of 600 mg once daily
for 9 days, reduced the mean AUC by 79% and Cmax by 71% of a single 5 mg dose of
axitinib in healthy volunteers. Co-administration of axitinib with strong CYP3A4/5 inducers
(e.g., rifampicin, dexamethasone, phenytoin, carbamazepine, rifabutin, rifapentin,
phenobarbital, and Hypericum perforatum [St. John's wort]) may decrease axitinib plasma
concentrations. Selection of concomitant medicinal products with no or minimal CYP3A4/5
induction potential is recommended. If a strong CYP3A4/5 inducer must be co-administered,
a dose adjustment of axitinib is recommended.

CONCLUSION
Recently targeted agents have changed the landscape for patients with advanced RCC.
Axitinib is an oral, potent multitargeted tyrosine kinase receptor inhibitor, which selectively
inhibits VEGFR-1, -2, and -3. It is metabolized primarily in the liver via the cytochrome P450
system and less than 1% of the drug is removed unchanged in the urine. Coadministration
with CYP3A4 and 1A2 inducers is contraindicated. Higher exposure to axitinib is associated
with higher efficacy indicated by decreased tumor perfusion and volume. Axitinib has
demonstrated antitumor activity with a favorable non-cumulative toxicity profile.

REFERENCES
[1] British National Formulary, accesed online at https://www.medicinescomplete. com/mc/b
nf/current/on 01/07/2015.
[2] Van Geel RM Beijnen JH Schellens JH. Concise drug review: pazopanib and axitinib. 20
12;17:1081–9.
[3] Marine Gross-Goupil, Louis François, Amandine Quivy, Alain Ravaud. Axitinib: A Revi
ew of its Safety and Efficacy in the Treatment of Adults with Advanced Renal Cell Carci
noma. Clin Med Insights Oncol. 2013; 7: 269–277.
In: The Easy Book of Cancer Pharmacology ISBN: 978-1-63485-038-4
Editor: Esther Una Cidon © 2016 Nova Science Publishers, Inc.

Chapter 5

BEVACIZUMAB. AVASTIN®

M. López-Gómez, B. García de Santiago, A. I. García,


A. M. Jiménez-Gordo and E. Casado
Medical Oncology Department,
University Hospital ―I
nfanta Sofia,‖ Madrid, Spain

ABSTRACT
Vascular endothelial growth factor (VEGF) is a molecule expressed in normal
tissues. It is involved in the process of angiogenesis. A VEGF ligand binds to receptors
on endothelial cells (such as VEGFR2) initiating the new vessel formation process [1-3].
Besides, the VEGFR family is primarily responsible for pro-angiogenic VEGF signalling
[4, 5].
But although VEGF is expressed in normal tissues, it is highly overexpressed in
many tumors [6], and therefore becomes a very attractive target for the development of
new agents.
Bevacizumab is designed to directly bind to VEGF extracellularly to prevent
interaction with VEGF receptors (VEGFRs) on the surface of endothelial cells, and
thereby might inhibit VEGF‘s angiogenic activity. It has been shown to have both
antivascular and anti-angiogenesis effects: with the regression of the existing tumor
vasculature its action results in a reduction of tumor size [7], and with the inhibition of
new and recurrent tumor vessel growth it also results in an inhibition of tumor growth [8].
Bevacizumab is indicated for the treatment of metastatic colorectal cancer (mCRC), non-
squamous non-small cell lung cancer (NSCLC), metastatic renal cell carcinoma,
persistent, recurrent or metastatic cervical cancer and platinum-resistant recurrent
epithelial ovarian, fallopian tube, or primary peritoneal cancer. Several randomized trials
have shown the improved overall survival and progression free survival in different
metastatic tumors when giving in combining with standard therapies (FOLFOX and
FOLFIRI in colon cancer, carboplatin and taxol in lung, cervical and ovarian cancer,
interferon alfa in renal cancer…). As a single agent it can be used in the treatment of
progressive glioblastoma after a prior chemotherapy schedule.


miriam.lopez@movistar.es.
38 M. López-Gómez, B. García de Santiago, A. I. García et al.

Some cautions must be considered to the use of anti-angiogenesis drugs: i.e,


bevacizumab is associated with a greater risk of hypertension, gastrointestinal
hemorrhage and perforation. Besides, the risk of stroke and other arterial events is
increased in patients receiving bevacizumab, especially in those aged 65 or older.

Keywords: avastin, bevacizumab, colorectal cancer, VEGF

INTRODUCTION
VEGF is a molecule involved in the process of angiogenesis which is expressed in
normal tissues [1-3] and highly overexpressed in many tumors [6]. When a VEGF ligand
binds to a VEGFR on endothelial cells it initiates the new vessel formation process [1-3].
Besides, the VEGFR family is primarily responsible for pro-angiogenic VEGF signalling
[4, 5]. Bevacizumab is designed to directly bind to VEGF extracellularly to prevent
interaction with VEGFRs on the surface of endothelial cells and inhibit angiogenic activity
[1-3]. Bevacizumab is indicated for the treatment of several tumors and various randomized
trials have shown an improved overall survival and progression free survival in different
metastatic cancers when giving in combination with standard therapies.
Some cautions must be taken into account with anti-angiogenesis drugs such as
hypertension, gastrointestinal haemorrhage and perforation or risk of stroke and other arterial
events which is higher especially in patients aged 65 or older.

DRUG CLASSIFICATION
Bevacizumab is a recombinant humanized monoclonal IgG1 antibody that binds to and
inhibits the biologic activity of human VEGF.

MECHANISM OF ACTION
Bevacizumab binds VEGF and prevents the interaction of VEGF to its receptors which
are located on the surface of endothelial cells.
As the interaction of VEGF with its receptors leads to endothelial cell proliferation and
new blood vessel formation, the administration of bevacizumab results in a reduction of
microvascular growth and an inhibition of metastatic disease progression.

PHARMACOKINETICS
Absortion Administered as an intravenous infusion.
Distribution The predicted time to reach steady state is 100 days.
Metabolism Bevacizumab catabolism takes place in endothelial cells and does not depend on renal or liver
elimination.
Excretion The clearance of bevacizumab varies by body weight, gender and tumor burden. Males and patients
with a higher tumor burden or a low albumine level have a higher clearance. The estimated half-life
is approximately 20 days (range 11-50).
Bevacizumab. Avastin® 39

MECHANISM OF RESISTANCE
Currently, there are not validated biological markers to indicate resistance to
antiangiogenic therapies in cancer. However, there are several studies (preclinical animal and
clinical trials) suggesting physiologic, circulating, intratumoral and imaging biomarkers that
are currently under clinical investigation.
A study on rectal cancer has reported that baseline levels of soluble VEGFR1 in plasma
are related to poor response to bevacizumab which could make it a potential biomarker of
intrinsic resistance [9].

INDICATIONS [10]
1. mCRC with intravenous 5-fluorouracil-based chemotherapy for first or second-line
treatment.
2. Non-squamous NSCLC with carboplatin and paclitaxel for first line treatment of
unresectable, locally advanced, recurrent or metatatic disease.
3. Metastatic breast cancer, with paclitaxel for treatment of patients who have not
received chemotherapy for metastatic HER2-negative breast cancer.
4. Glioblastoma, as a single agent for patients with progressive disease following prior
therapy.
5. Platinum-Resistant Recurrent Epithelial Ovarian, Fallopian Tube, or Primary
Peritoneal Cancer in combination with paclitaxel, pegylated liposomal doxorubicin,
or topotecan.
6. Persistent, recurrent or metastatic cervical cancer in combination with paclitaxel and
either cisplatin or topotecan.
7. Metastatic renal cell carcinoma in combination with interferon alfa.

DOSAGES [10]
The recommended doses are as follows:

1. In mCRC 5 mg/kgr or 10 mgr/kg every 2 weeks when used in combination with


intravenous 5-FU-based chemotherapy.
2. In non-squamous NSCLC 15 mg/kg every 3 weeks.
3. In metastatic breast cancer 10 mg/kg every 2 weeks.
4. In glioblastoma the recommended dose is 10 mg/kg every 2 weeks.
5. In ovarian, fallopian tube, or primary peritoneal cancer 10 mg/kgr every 2 weeks in
combination with paclitaxel, pegylated liposomal doxorubicin, or weekly topotecan
and 15 mg/kg every 3 weeks when combined with topotecan every 3 weeks.
6. In metastatic cervical cancer 15 mg/kg in combination with paclitaxel and either
cisplatin or topotecan.
40 M. López-Gómez, B. García de Santiago, A. I. García et al.

METHODS OF ADMINISTRATION/PREPARATION [10]


Bevacizumab is available as:

 100 mg per 4 ml single-use vial


 400 mg per 16 ml single-use vial

Avastin must never be administered or mixed with dextrose solutions.


Bevacizumab must always be administered as an iv infusion and never as an iv push or
bolus. It must never be administered or mixed with dextrose solution. The first infusion must
be administered over 90 minutes, and if it is well tolerated the second infusion must be
administered over 60 minutes. The following infusions can be administered over 30 minutes
if the previous have been well tolerated.
Bevacizumab must never be initiated for at least 28 days following major surgery and
after the surgical incision has fully healed.

SPECIAL INFORMATION AND CAUTIONS [10]


Contraindications

Hypersensitivity to the active substance or to any of the excipients listed below:

 Trehalose dihydrate
 Sodium phosphate
 Polysorbate 20
 Water for injections

Hypersensitivity to cells derived from Chinese hamster ovary (CHO) products, or other
human or humanized recombinant antibodies.

 Pregnancy

Elderly Patients

No dose adjustment is needed.


Patients aged ≥65 years have shown higher incidence of side-effects such as fatigue,
sepsis, DVT, hypertension, MI, congestive heart failure (CHF), diarrea/constipation, anorexia,
leukopenia, anemia, hypokalemia/hiponatremia, emesis, ileus, proteinuria, GI haemorrhage,
oedema, epistaxis, increased cough and voice alteration.
The overall incidence of ATE was increased in patients receiving Avastin regardless of
age. However, the incidence was higher in patients aged ≥65 years.
Bevacizumab. Avastin® 41

Pediatric Patients

Safety, effectiveness and pharmacokinetic profile of Avastin in pediatric patients have


not been established. There is insufficient information to determine the safety and efficacy of
Avastin in children with glioblastoma.

Renal Impairment

No data about safety and efficacy.

Hepatic Impairment

No data about safety and efficacy.

Immunisations

Live vaccines should not be applied while taking the treatment or for at least 6 months
afterwards. Other vaccines can be administered, though may not give as much protection as
usual. In any case, it is safe to be in contact with other people who have had live vaccines as
injections. There can be problems with oral vaccines. Any contacts with someone who has
had oral polio, cholera or typhoid vaccination recently, should be avoided.

Lactation

Breast-feeding is not recommended as potential risk for breast fed infant although no data
are available.

Patients of Reproductive Potential

Effective contraception should be used during treatment with Avastin and for 6 months
following the last dose of Avastin.

WARNINGS [10]
Gastrointestinal (GI) Perforations and Fistulae

Serious and sometimes fatal GI perforation occurs between 0.3-3.2%. The typical
presentation includes abdominal pain, nausea, emesis, constipation and fever and can be
42 M. López-Gómez, B. García de Santiago, A. I. García et al.

complicated by intra-abdominal abscess, fistula formation and the need for diverting
ostomies.
Most case occurred within the first 50 days of initiation of Avastin. Its use should be
avoided in patients with ovarian cancer who have evidence of recto-sigmoid involvement by
pelvic examination or bowel involvement on CT scan or clinical symptoms of bowel
obstruction.
Permanently discontinue Avastin in patients with GI perforation.
GI fistulae have been reported in 2% of patients with mCRC and ovarian cancer.

Non-Gastrointestinal Fistulae

Serious and sometimes fatal fistula formation involving tracheo-esophageal,


bronchopleural, biliary, vaginal, renal and bladder sites may occur (<1%). Most events
occurred within the first 6 months.
Permanently discontinue Avastin in patients with tracheoesophageal fistula or any Grade
4 fistula. Discontinue Avastin in patients with fistula formation involving an internal organ.

Surgery and Wound Healing Complications

Avastin impairs wound healing in animal models. In clinical trials, administration of


Avastin was not allowed until at least 28 days after surgery.
Discontinue Avastin in patients with wound healing complications requiring medical
intervention.
The appropriate interval between the last dose of Avastin and elective surgery is
unknown; however, the half-life of Avastin is estimated to be 20 days. Suspend Avastin for at
least 28 days prior to elective surgery. Do not administer Avastin until the wound is fully
healed.
Necrotizing fasciitis including fatal cases, has been reported; it is usually secondary to
wound healing complications, GI perforation or fistula formation. Discontinue Avastin
therapy in patients who develop necrotizing fasciitis.

Arterial Thromboembolic Events

Serious, sometimes fatal, arterial thromboembolic events (ATE) including cerebral


infarction, transient ischemic attacks (TIA), myocardial infarction (MI), angina, and a variety
of other ATE may occur. The incidence of Grade ≥3 ATE in the Avastin containing arms was
2.6%. The risk is higher if a history of ATE, diabetes or >65 years.
Discontinue Avastin in patients who experience a severe ATE. The safety of resumption
of this therapy after resolution of an ATE has not been studied.
Bevacizumab. Avastin® 43

Venous Thromboembolic Events

Patients treated for persistent, recurrent, or metastatic cervical cancer with Avastin may
be at increased risk of venous thromboembolic events.

Haemorrhage

Avastin has got two distinct patterns of bleeding:

1. Minor haemorrhage, most commonly Grade 1 epistaxis.


2. Serious or fatal haemorrhagic events such as haemoptysis, GI bleeding, hematemesis,
central nervous system (CNS) haemorrhage, epistaxis and vaginal bleeding. The
incidence of Grade ≥3 haemorrhagic events ranged from 0.4 to 6.9%.

Serious or fatal pulmonary haemorrhage was observed in 31% patients with squamous
cell histology and 4% patients with non-squamous NSCLC receiving Avastin and
chemotherapy compared to none receiving chemotherapy alone.
In clinical studies in NSCLC with CNS metastases who completed radiation and surgery
more than 4 weeks prior to the start of Avastin symptomatic Grade 2 CNS haemorrhage was
documented in 1.2%.
Avastin should not be administered to patients with recent history of haemoptysis
of ≥1/2 teaspoon of red blood. Discontinue Avastin in patients with haemorrhage.

Hypertension

The incidence of severe hypertension is increased. Blood pressure should be monitored


every 2-3 weeks during treatment and an appropriate anti-hypertensive therapy started if
needed.
Temporarily suspend Avastin in patients with severe hypertension that is not controlled
with medical management.
Discontinue Avastin in patients with hypertensive crisis or hypertensive encephalopathy.

Posterior Reversible Encephalopathy Syndrome (PRES)

PRES has been reported with an incidence of <0.5% in clinical studies. The onset of
symptoms occurred from 16 hours to 1 year after initiation of Avastin. PRES is a neurological
disorder which can present with headache, seizure, lethargy, confusion, blindness and other
visual and neurologic disturbances. Mild to severe hypertension may be present. Magnetic
resonance imaging (MRI) is necessary to confirm the diagnosis of PRES.
Discontinue Avastin in patients developing PRES. Symptoms usually resolve or improve
within days, although some patients have experienced ongoing neurologic sequelae. The
safety of reinitiating Avastin therapy in patients previously experiencing PRES is not known.
44 M. López-Gómez, B. García de Santiago, A. I. García et al.

Proteinuria

The incidence and severity of proteinuria is increased. Nephrotic syndrome


occurred in <1%.
Proteinuria should be monitored by dipstick urine analysis for the development or
worsening with serial urinalyses during Avastin therapy. Patients with a 2 + or greater urine
dipstick reading should undergo further assessment with a 24-hour urine collection.
Avastin should be suspended for ≥2 grams of proteinuria/24 hours and resume when
proteinuria is <2 gm/24 hours. Discontinue Avastin in patients with nephrotic syndrome.

Infusion Reactions

Infusion reactions include hypertension, hypertensive crises associated with neurologic


signs and symptoms, wheezing, oxygen desaturation, Grade 3 hypersensitivity, chest pain,
headaches, rigors, and diaphoresis. In clinical studies, total infusion reactions with the first
dose were <3% and severe reactions occurred in 0.2% of patients.
Stop infusion if a severe infusion reaction occurs and administer appropriate medical
therapy.

Embryo-fetal Toxicity

Avastin may cause fetal harm based on findings from animal studies (congenital
malformations). Pregnant women should be advised of the potential risk to a fetus.

Ovarian Failure

Females should be informed of the risk of ovarian failure prior to starting treatment. Long
term effects of Avastin exposure on fertility are unknown.

TOXICITIES [10]
System organ class Very common Common Uncommon Rare
(≥1/10) (≥1/100 to < 1/10) (≥1/1000 (≥1/10,000
to <1/100) and <1/1000)
Vascular disorders Hypertension, deep Pulmonary embolism,
thrombosis, hypoxia, epistaxis,
embolism, bleeding.
deep arterial
thromboembolism
Skin and Skin hypo- Palmar-plantar
subcutaneous pigmentation, erythrodysesthesia
tissue disorders exfoliative dermatitis,
delayed wound
Bevacizumab. Avastin® 45

healing,
System organ class Very common Common Uncommon Rare
(≥1/10) (≥1/100 to < 1/10) (≥1/1000 (≥1/10,000
to <1/100) and <1/1000)
Infections and Febrile neutropenia, Abscess, sepsis, Necrotizing
infestation urinary tract infection fasciitis
disorders
Metabolism and Dehydration
nutrition disorders
Nervous system Dysarthria, headache, Syncope, Posterior
disorders dysgeusia, axonal sommnolency, reversible
neuropathy Cerebrovascular encephalopathy
stroke, syndrome
Cardiac disorders Heart failure,
supraventricular
tachycardia
Gastrointestinal Stomatitis, GI perforation, ileo
disorders constipation, nausea, paraliticus,
vomiting, anorexia, abdominal pain,
rectal haemorrhage,
mucosae
inflammation
Hepatobiliary
disorders
Respiratory, Dyspnea, Lung bleeding,
thoracic and haemoptysis,
mediastinal dysphonia
disorders
Renal and urinary Proteinuria,
disorders
General disorders Asthenia, fever, pain Fistula formation
and administration
site conditions
Immune system Hypersensitivity
disorders
Investigations Leukopenia,
neutropenia,
thrombocytopenia,
Eye and nose Eye irritation and eye
disorders watering, rhinitis
Gynaecological
disorders
Musculoskeletal Arthralgia Myalgia
Very rare
Hypertensive encephalopathy
Unknown frequency
Renal thrombotic microangiopathy
Pulmonary hypertension
Nasal septum perforation
GI ulcer
Gallbladder perforation
Osteonecrosis of the jaw
Ovarian failure
46 M. López-Gómez, B. García de Santiago, A. I. García et al.

DOSE MODIFICATIONS [10]


There are no recommended dose reductions.
Bevacizumab must be discontinued for:

 Gastrointestinal perforations (fistula formation in the gastrointestinal tract, intra-


abdominal abscess).
 Fistula formation involving an internal organ.
 Wound dehiscence and wound healing complications requiring medical intervention.
 Necrotizing fasciitis.
 Serious haemorrhage.
 Severe ATE or life-threating venous thromboembolism (such as pulmonary
embolism)
 Hypertensive crisis is an indication to stop avastin permanently.
 PRES.
 Nephrotic syndrome.

Bevacizumab must be temporarily suspended for:

 At least 4 weeks prior to elective surgery. Bevacizumab should not be initiated for at
least 28 days following surgery and until the surgical wound is fully healed.
 Severe hypertension not controlled with medical management.
 Moderate to severe proteinuria pending further evaluation. Avastin must be
suspended for ≥2 grams of proteinuria/24 hours and resume when proteinuria
is <2 grams/24 h.
 Severe infusion reactions.

INTERACTIONS [10]
 Panitumumab

Using panitumumab together with bevacizumab plus other chemotherapy drugs is not
recommended. In clinical trials these combinations has led to a worse treatment outcome.

 Samarium 153 lexidronam

The combination of both drugs may increase the risk of side-effects that affect the bone
marrow function.

 Sunitinib

As the combination is associated with a rare type of anemia.


Bevacizumab. Avastin® 47

 Zoledronic acid

The combination of both drugs might increase the risk of ostenecrosis of the jaw.

 Pegfilgrastim

Using this drug during or too soon after completion of a course of bevacizumab may alter
the effects of either medication; therefore pegfilgrastim should generally not be given from 14
days before until 24 hours after treatment with bevacizumab.

 Filgrastim

Similarly, filgrastim should generally not be given within 24 hours before or 24 hours
after treatment with bevacizumab as they might interfere with each other.

 Palifermin

It is used to treat painful mouth ulcers that can occur from chemotherapy. However, the
timing of the dosing of palifermin relative to chemotherapy is important. Palifermin should
generally not be used within 24 hours before or after chemotherapy.

 Topotecan

Using topotecan together with bevacizumab may increase the risk of side-effects that
affect the bone marrow function, resulting in low numbers of different types of blood cells.

CONCLUSION
Bevacizumab has been the first FDA approved antiangiogenic agent and its indications
have been widely increased in recent years [4, 5]. Although its toxicity is lower than other
cytostatic drugs, there are some issues of concern such as hypertension, venous
thromboembolism events, bleeding, fistula formation, delayed wound healing and proteinuria.
It is generally used in combination with standard cytototoxic drugs, except in progressive
glioblastoma where it is approved as a single agent [10].
Recommendations to patients must include monitor blood pressure regularly, and treat
with anti- hypertensive therapy (preferably with ACE inhibitors, angiotensin II receptor
antagonists, and calcium channel blockers). Dipstick urine test to rule out proteinuria must be
performed prior to each bevacizumab administration. If severe and persistent proteinuria is
diagnosed bevacizumab use must be discontinued and the patient should be referred to a
nephrologist [10]. Besides, female patients of reproductive potential must be informed of the
risk of ovarian failure prior to starting treatment with bevacizumab. However, an early
recognition of its potential side effects makes bevacizumab an easy-to-administration drug,
with a very manageable secondary events profile that has resulted in an increase of survival in
many different scenarios.
48 M. López-Gómez, B. García de Santiago, A. I. García et al.

REFERENCES
[1] Folkman J. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: Principles and
Practice of Oncology. Vol 2. 7th ed. Philadelphia, PA: Lippincott Williams and Wilkins;
2005:2865-2882.
[2] Hanrahan V, Currie MJ, Gunningham SP, Morrin HR, Scott PA, Robinson BA et al.
The angiogenic switch for vascular endothelial growth factor (VEGF)-A, VEGF-B,
VEGF-C and VEGF-D in the adenocma-carcinoma sequence during colorectal cancer
progression. J. Pathol. 2003, 200(2):183-94.
[3] Rini BI, Small EJ. Biology and clinical development of vascular endothelial growth
factor-targeted therapy in renal cell carcinoma. J Clin Oncol 2005; 23(5):1028-43.
[4] Hicklin DJ, Ellis LM. Role of the vascular endothelial growth factor pathway in tumor
growth and angjogenesis. J Clin Oncol, 2005; 23(5): 1011-27.
[5] Ferrara N, Hillan KF, Gerber HP, Novotny W. Discovery and development of
bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov 2004:
3(5):391-400.
[6] Bergers G, Benjamin LE. Tumorigenesis and the angiogenic switch. Nat Rev Cancer,
2003; 3(6):401-10.
[7] Yanagisawa M, Yorozu K, Kurasawa M, Nakano K, Furugaki K, Yamashita Y et al.
Bevacizumab improves the delivery and efficacy of paclitaxel. Anticancer drugs, 2010,
21(7):687-94.
[8] Bagri A, Berry L, Gunter B, Singh M, Kasman I, Damico LA et al. Effects of anti-
VEGF treatment duration on tumor growth, tumor regrowth and treatment efficacy.
Clin Cancer Res, 2010:16(15):3887-900.
[9] Kan V Lu, Gabriele Bergers. Mechanisms of evasive resistance to anti-VEGF therapy
in Glioblastoma. CNS Oncol. 2013, 2(1): 49–65.
[10] EMA, 2015. Bevacizumab. Summary of Product Characteristics. pp.: 1-54.
In: The Easy Book of Cancer Pharmacology ISBN: 978-1-63485-038-4
Editor: Esther Una Cidon © 2016 Nova Science Publishers, Inc.

Chapter 6

BLEOMYCIN. BLEO-KYOWA. BLENOXANE

B. Masters
Specialist Registrar in Clinical Oncology,
Nottingham City Hospital, Nottingham, UK

ABSTRACT
Bleomycin is an antitumour antibiotic, which exhibits its cytotoxic action by
inducing strand breaks in DNA molecules. It exerts this effect in the presence of a metal
ion and oxygen, causing free radical production, which damage the DNA strand.
Bleomycin can also cleave RNA molecules by the same mechanism, due to their similar
structure thus also inhibiting protein synthesis. It is regularly used in combination with
other chemotherapy agents to treat germ cell tumours and Hodgkin‘s lymphoma. It can
also be used to treat non-Hodgkin‘s lymphomas and squamous cell carcinomas of the
head and neck, cervix, vulva and penis and as a sclerosing agent for chemical
pleurodesis.
The most common adverse effects associated with bleomycin are anorexia, nausea,
vomiting, interstitial pneumonitis, alopecia, skin erythema, nail deformation, scratch
dermatitis, scleroderma and fever. Hypersensitivity reactions can also occur. Pulmonary
toxicity induced by bleomycin can be life threatening and monitoring for signs and
symptoms, in combination with pulmonary function testing and regular chest radiographs
is essential.

Keywords: bleomycin, anticancer antibiotics

INTRODUCTION
Bleomycin or bleomycin sulphate is a mixture of glycopeptide molecules isolated from a
strain of bacteria called streptomyces verticillus. Over 200 members of the bleomycin family
have been isolated since being discovered in the 1960s [1]. Bleo-Kyowa and blenoxane are a


Email: ben.masters240@gmail.com.
50 B. Masters

mixture of bleomycin glycopeptides that predominately contain bleomycins A2 and B2.


Bleomycin has both antitumour and antibacterial activity, and is used to treat a variety of
tumours, mostly in combination with other chemotherapy agents.

CLINICAL PHARMACOLOGY
Drug Classification

Antitumour antibiotic.

Mechanism of Action

Bleomycin has been widely shown to damage DNA by inducing single strand breaks [2-
4]. These breaks tend to occur at guanosine-cytosine and guanosine-thymidine rich portions
of DNA. The cytotoxic effect of bleomycin predominantly occurs in the G2 phase of the cell
cycle.
Structurally bleomycin consists of four domains: the metal binding domain, the linker
domain, the carbohydrate domain and the C-terminal tail. The C-terminal tail is required for
DNA binding, and is connected to the metal binding domain via the linker domain. The
carbohydrate side chain is connected to the metal binding region, and is believed to be
essential for DNA cleaving efficiency [5]. Although the administered form of bleomycin is
metal-free, the presence of metal ions is essential for nucleic acid damage [6]. The most
widely studied metal ion is Fe (II), but bleomycin complexed with copper, manganese, cobalt,
ruthenium and nickel ions can also cause DNA damage [7].
The cytotoxic action of bleomycin is due to the presence of a metal ion (Fe) and oxygen,
forming an activated bleomycin complex [8]. The activated bleomycin extracts a hydrogen
atom from the deoxyribose sugar of the nucleic acid, forming a sugar-centered free radical.
This radical reacts further by cleaving the DNA strand or by releasing free nucleobases [9].
Double stranded DNA breaks can also be created by the binding of a single bleomycin
molecule, but are much less common than single strand breaks [10].
Bleomycin may also exert a cytotoxic effect by causing oxidative, free radical damage to
RNA molecules. This occurs by the same mechanism as bleomycin-induced DNA damage
and leads to inhibition of cellular protein synthesis [11].

Pharmacokinetics

Absorption Poor oral bioavailability


Distribution <10% bound to plasma proteins. Low levels found in bone marrow*
Metabolism Rapidly deactivated in tissues by bleomycin hydrolase
Half-life: 3 hours
Excretion 50-70% excreted unchanged in urine**
*This is why (unlike other chemotherapy agents) bone marrow suppression is an uncommon toxicity of
bleomycin use. **Renal impairment leads to drug accumulation.
Bleomycin. Bleo-Kyowa. Blenoxane 51

Mechanism of Resistance

Bleomycin activity can be inhibited in normal tissues by the presence of the bleomycin
hydrolase enzyme. Bleomycin hydrolase is a cysteine protease, which inhibits the action of
bleomycin by replacing a terminal amine with a hydroxyl group [12].
Lower concentrations of bleomycin hydrolase have been found in cells of the lung and
skin, which may explain why these tissues are particularly sensitive to bleomycin toxicity.
Germ cell tumours with increased expression of the bleomycin hydrolase gene have been
associated with reduced survival and a higher rate of earlier relapse [13].
Up-regulation of DNA repair pathways is another mechanism by which tumours can
develop resistance to bleomycin. AP endonuclease (Ape-1 or Ref-1) is a DNA base excision
repair enzyme and up-regulation of this enzyme has been associated with increased resistance
to bleomycin [14]. There are several other potential mechanisms by which tumours can
develop resistance to bleomycin including altered cell uptake and efflux, and also elevated
antioxidant levels [15].

INDICATIONS
1. Germ cell tumours
2. Hodgkin‘s lymphoma
3. Non-Hodgkin‘s lymphoma
4. Squamous cell carcinoma of the head and neck, skin, cervix, vulva and penis
5. Sclerosing agent for chemical pleurodesis.

DOSAGES
Bleomycin dosing has been documented in several ways within the literature. For
example the standard dose of Bleo-Kyowa is 15,000IU or 15 x 103IU, which is often
simplified to 15 units. Historically bleomycin has also been dosed in milligrams (15 units
would be equivalent to 15mg), but this has been phased out. For simplicity I have used units,
rather than thousands of units of bleomycin for my examples of bleomycin dosing.

Intravenous/Intramuscular

Germ Cell Tumours


BEP chemotherapy regime - given in combination in a 3 or 5 day regime with etoposide
and a platinum chemotherapy agent (cisplatin) [16, 17]

 3 day regime: Bleomycin - day 1, 8 and 15 (or 2, 9 and 16) – 30 units/m2 or 30 units
q21.
 5 day regime: Bleomycin - day 1, 8 and 15 (or day 2, 9 and 16) – 30 units/m2 or 30
units q21.
52 B. Masters

Intravenous

Hodgkin’s Lymphoma
ABVD chemotherapy regime – given in combination with doxorubicin, vinblastine and
dacarbazine [16, 17]

 Day 1 – 10 units/m2 q14 or


 Day 1 and 15 – 10 units/m2 q28

Intra-Pleural

Sclerosing Agent for Chemical Pleurodesis


60 units injected into the pleural cavity. When injected for 60 minutes this has shown to
have a 60% success rate at preventing malignant effusion re-accumulation. Talc pleurodesis
has an 80% success rate at preventing re-accumulation of malignant effusions and is
consequently more commonly used for this indication.

METHODS OF PREPARATION/ADMINISTRATION
Intravenous/Intra-Arterial

The required dose is dissolved in 5-200ml 0.9% saline solution. This is either injected
slowly (to prevent vascular pain) or added to the reservoir of an intravenous infusion. A slow
infusion of bleomycin dissolved in 0.9% saline solution is used for intra-arterial
administration.

Intramuscular

The required dose is dissolved in 5ml 0.9% saline solution. If pain occurs at the injection
site, 1% lignocaine can be used as a solvent. Avoid repeated injection into the same site or
into innervated sites.

Intrapleural

Following pleural drainage, 60 units of bleomycin is dissolved in 100ml 0.9% saline


solution and introduced into the cavity via the drain or by injection. Following instillation, the
drain or needle may be withdrawn. Administration may be repeated up to a maximum dose of
500 units.
Bleomycin. Bleo-Kyowa. Blenoxane 53

Subcutaneous

The required dose is dissolved in 0.9% saline solution to make a 1-3units/ml bleomycin
solution.

SPECIAL INFORMATION AND CAUTIONS


Contraindications

 Bleomycin is contra-indicated in patients with acute pulmonary infection or chest x-


ray findings suggesting of diffuse fibrotic changes or greatly reduced lung function.
 Known hypersensitivity or an idiosyncractic reaction to Bleomycin sulphate.

Elderly

The effect of age on the pharmacokinetics of bleomycin has not been evaluated.

Pediatric

In children with normal renal function, plasma concentrations of Bleomycin decline


biexponentially as in adults. The volume of distribution and terminal half-life of Bleomycin in
children appears comparable to that in adults.

Renal Impairment

Renal insufficiency alters Bleomycin elimination. The terminal elimination half-life


increases exponentially as the creatinine clearance decreases. Therefore a dose reduction is
recommended for patients with creatinine clearance values of <50 mL/min.

Hepatic Impairment

The effect of hepatic insufficiency on the pharmacokinetics of Bleomycin has not been
evaluated.

Immunisations

Live vaccines should not be given to patients whilst receiving chemotherapy, and for at
least 6 months afterwards. Although other vaccines may be administered, they may not be as
effective when given during this period. It is safe, however, for patients receiving
54 B. Masters

chemotherapy to be in contact with others who have been injected with live vaccines.
However, close contact with patients who have recently received oral vaccinations such as
polio, cholera or typhoid should be avoided.

Pregnancy and Breast-Feeding

Bleomycin can cause fetal harm when administered to a pregnant woman. Patients of
reproductive potential should be advised to use highly effective contraception during
treatment. Bleomycin should not be given to pregnant or breast-feeding patients.

WARNINGS
Pulmonary Toxicity

This is dose (>400 units – total dose) and age-related (>70 years). Smokers and those on
oxygen therapy are also at increased risk. It occurs in 10% of treated patients and in 1% of
patients; bleomycin induced pneumonitis can lead to pulmonary fibrosis and death.
Signs and symptoms of pulmonary toxicity include cough, breathlessness, fine crackles
on auscultation and changes consistent with fibrosis on chest x-ray. Pulmonary function
testing and measurement of carbon monoxide diffusion ability should be obtained before
during, and following the completion of the chemotherapy regime.
A reduction of more than 15% in pulmonary function testing requires discontinuation of
the drug. A chest x-ray prior to each cycle of chemotherapy should also be performed.
Bleomycin should be stopped in all patients suspected of developing pulmonary toxicity.
Oxygen therapy should be avoided in all patients treated with bleomycin, unless they
become profoundly hypoxic. Non-invasive ventilation may be helpful in acutely hypoxic
patients to limit their oxygen requirements.
Concurrent radiotherapy should be avoided as this may worsen bleomycin induced
pulmonary toxicity.
If bleomycin induced respiratory complications occur the drug should be stopped and the
patient should be treated with high dose corticosteroids (prednisolone 0.75-1mg/kg) and
broad-spectrum antibiotics.
Bleomycin induced pneumonitis is thought to resolve in the majority of patients over
time, with improvements in pulmonary function and radiological appearance at >15 months
[18].

Idiosyncratic Reactions

Similar to anaphylaxis, these reactions have been reported in approximately 1% of


lymphoma patients treated with bleomycin. Since these usually occur after the first or second
dose, careful monitoring is essential following these doses.
Bleomycin. Bleo-Kyowa. Blenoxane 55

Renal and Hepatic Toxicity

Cases of both renal and hepatic deterioration have also infrequently been reported, and
may occur at any time after initiation of therapy.

TOXICITIES
System organ Very common Common Uncommon Rare
class (≥1/10) (≥1/100 to <1/10) (≥1/1000 to (≥1/10,000 and
<1/100) <1/1000)
Vascular Vein wall Hypotension, local
disorders hypertrophy, thrombophlebitis
venous stenosis post intravenous
administration
Nervous Headache Dizziness
system
disorders
Hepatobiliary Hepatic toxicity
disorders
Gastrointestinal Anorexia, nausea, Angular stomatitis Diarrhoea
disorders vomiting
Respiratory, Interstitial Pulmonary fibrosis
thoracic and pneumonitis
mediastinal
disorders
Renal and Renal toxicity,
urinary urinary retention
disorders
General Fever/rigors Hypersensitivity Pain at tumour site
disorders and reaction (with fevers
administration and chills),
site conditions haemorrhage
Skin and nail Nail deformation, Urticarial reaction, Injection site
disorders alopecia, skin erythroderma induration
erythema/hypertrophy/
hyperpigmentation,
scratch dermatitis,
scleroderma
Blood disorders Leucopenia,
myelosupression
Very rare
Anaphylactoid type reactions
Hyperpyrexia
Cardiorespiratory collapse
Chest pain (pleuro-pericarditis)
Frequency unknown
Pancytopenia Embolism Cerebral infarction
Thrombocytopenia Thrombosis Anaemia
Myocardial infarction Raynaud‘s phenomenom Neutropenia
56 B. Masters

DOSE MODIFICATIONS
 Renal impairment: reduced clearance may occur in patients with renal impairment.
Currently no guidelines for specific dose adjustments have been established.
However a dose reduction in patients with creatinine clearance values of <50 mL/min
is advised.
 Liver impairment: no dose adjustment required.

INTERACTIONS
 Oxygen – enhances pulmonary toxicity by increasing free radical production, which
can be potentially life threatening. Air driven continuous positive airway pressure has
been used to treat acutely hypoxic patients on bleomycin chemotherapy regimes in
some centers.
 Phenothiazines - enhance activity and toxicity of bleomycin through competition
with cytochrome P450.
 Cisplatin – decreases renal clearance of bleomycin and may increase toxicity
 Concurrent/previous radiotherapy to thorax– enhances the pulmonary toxicity of
bleomycin.

CONCLUSION
Bleomycin is an antitumour antibiotic that has been used to treat cancer for many years.
Due to its molecular structure it is able to bind to DNA, and in the presence of a metal ion and
oxygen it is able to form free radicals, which cause breaks in the DNA structure. It can also
inhibit protein synthesis by binding and damaging RNA by the same mechanism. Bleomycin
can be administered by multiple routes to treat cancer and can also be given intra-pleurally to
prevent re-accumulation of malignant effusions.
Bleomycin is deactivated in normal tissues by the enzyme bleomycin hydrolase, and
increased gene expression of this enzyme has lead to resistance in some tumours. A lower
concentration of this enzyme in lung tissues is the likely cause for bleomycin‘s potentially
fatal lung damaging toxicity. The risk of lung toxicity increases with age, total dose, smoking
history and oxygen therapy. All patients receiving bleomycin therapy should therefore been
regularly monitored for signs of developing this side-effect.

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and overexpression in NT2 cells confers resistance to Bleomycin and radiation. Cancer
Res. 2001. 61; 2220.
[15] Wang Q, Cui K et al. Resistance to Bleomycin in cancer cell lines Is characterized by
prolonged doubling time, reduced DNA damage and evasion of G2/M Arrest and
apoptosis. PLoS One. 2013; 8(12).
[16] Derby-Burton Local Cancer Network, local network oncology regimens.
https//www.derbyhospitals.nhs.uk/primary/pharmacy/chemotherapy-services/derby-
burton-cancer-network/local-network-oncology-regimens.
[17] De Wit R, Roberts J. et al. Equivalence of three of four cycles of Bleomycin, Etoposide,
and cisplatin chemotherapy and of a 3- or 5- day schedule in good-prognosis germ cell
cancer: a randomized study of the European Organization for Reseach and Treatment of
Cancer Genitourinary Tract Cancer Co-operative Group and the Medical Research
Council. J. Clin Urol. 2001. 19, 1629-1640.
[18] Reinert T, Serodio da Rocha Baldotto C, Bleomycin-Induced Lung Injury. J of Cancer
Res. 2013. Article ID 480608.
In: The Easy Book of Cancer Pharmacology ISBN: 978-1-63485-038-4
Editor: Esther Una Cidon © 2016 Nova Science Publishers, Inc.

Chapter 7

CABAZITAXEL. JEVTANA®

E. Una Cidon
Department of Medical Oncology. Royal Bournemouth Hospital
NHS Foundation Trust, UK

ABSTRACT
Cabazitaxel is a semisynthetic taxane which binds to tubulin and promotes its
assembly into microtubules [1]. At the same time, it inhibits disassembly and produces
microtubule stabilization and inhibition of mitotic and interphase cellular functions [1]. It
is indicated in patients with castration-resistant prostate cancer (CRPC), when they
become refractory to docetaxel. The approval was based on an advantage in overall
median survival when compared to mitoxantrone with prednisone. Common side effects
include neutropenia and diarrhea and close monitoring to start prompt treatment is needed
[2].

Keywords: cabazitaxel, taxanes, antimicrotubules

INTRODUCTION
Cabazitaxel is a semisynthetic taxane using a precursor molecule extracted from yew tree
needles [1, 2].
It is an antimicrotubule agent which binds to tubulin and promotes its assembly into
microtubules and simultaneously inhibits disassembly. This results in microtubule
stabilization and finally in the inhibition of mitotic and interphase cellular functions [1]. It has
come to increase the therapeutic options in patients with castration-resistant prostate cancer
(CRPC), when they become refractory to docetaxel, since its approval in 2010 by the Food
and Drug Administration (FDA). This approval was based on the TROPIC study which


Esther Una Cidon, aunacid@hotmail.com; Esther.unacidon@rbch.nhs.uk.
60 E. Una Cidon

showed an overall median survival benefit of 2.4 months compared to mitoxantrone and with
prednisone [2].
Common side effects include neutropenia and diarrhea and close monitoring to start
prompt treatment is needed [1-4].

CLINICAL PHARMACOLOGY
Drug Classification [1, 2]

Antineoplastic drug. Antimicrotubule.

Mechanism of Action [1-4]

It binds to tubulin and promotes its assembly into microtubules and simultaneously
inhibits disassembly. This results in microtubule stabilization, which results in the inhibition
of mitotic and interphase cellular functions.

Pharmacokinetics [1, 3]

Absorption Maximum plasma concentration is 226 ng/mL which was reached in 1 hour (Tmax)
AUC 991 ng.h/ml
Distribution Volume distribution is 4,870 L at steady state
Protein bound is 89-92%; mainly albumin (82%)
Metabolism >95% in the liver by CYP3A (mainly) and by CYP2C8 (less), P-gp substrate;
7 metabolites (3 active) detected in plasma; 20 metabolites detected in faeces/urine
Excretion Faeces (76%), urine (3.7%)
Half-Life is 95 hours

Mechanism of Resistance [2]

Cabazitaxel is a novel taxane with poor affinity for P-glycoprotein (P-gp), an ATP-
dependent drug efflux pump.
Cancer cells that express P-gp become resistant to taxanes, and the effectiveness of
docetaxel can be limited by its high substrate affinity for P-gp.

Indications [1, 3, 4]

Prostate cancer
In combination with prednisone for hormone-refractory metastatic prostate cancer
previously treated with a docetaxel-containing regimen.
Cabazitaxel. Jevtana® 61

Dosages [1, 3, 4]

25 mg/m2 every 3 weeks. Give it with prednisone 10 mg orally daily.

METHODS OF PREPARATION/ADMINISTRATION [1, 3, 4]

Step 1 (1st Dilution)

Mix cabazitaxel 60 mg/1.5 mL vial with entire contents of supplied diluent. Once
reconstituted, resultant solution contains 10 mg/mL. Gently mix the diluted solution by
repeated inversions for at least 45 seconds to assure full mixing but do not shake.

Step 2 (2nd Dilution)

Withdraw recommended dose from 1st dilution and further dilute into sterile 250 mL
PVC-free container (glass, polyolefin) of either 0.9% NaCl or dextrose 5% solution for
infusion. The final concentration will range between 0.1-0.26 mg/mL.

Stability
Do not use PVC containers or polyurethane infusions sets for preparation or
administration. The 1st diluted solution in vial should be used immediately (within 30 min)
and discard unused product. The 2nd dilution in infusion bag should be used within 8 hours at
environment temperature, including infusion time, or for a total of 24 hours if refrigerated.

Premedication
30 minutes before each cabazitaxel, an antihistamine, a steroid and H2-antagonist iv
should be administered.

Administration
It should be administered over one hour. Use an in-line filter (0.22 micron pore size)
during administration.

Special Information and Cautions [1, 3, 4]

Contraindications
 Hypersensitivity to the drug or to other taxanes such as paclitaxel or docetaxel or its
excipients included polysorbate 80.
 Severe liver impairment (total bilirubin >3 upper limit normal)
62 E. Una Cidon

Elderly
No dose adjustment is needed. Neutropenia and febrile neutropenia are more frequent.
Monitor closely.

Pediatric
Not established efficacy or safety in this population.

Renal
No dose adjustment if mild to moderate renal impairment.

Hepatic
If mild hepatic impairment (bilirubin >1-≤ 1,5 ULN or AST >1,5), dose should be
reduced to 20 mg/m2. Caution and close surveillance to these patients.
If moderate hepatic impairment (bilirrubin >1.5-≤ 3 ULN), maximum tolerated dose was
15 mg/m2. However, limited data about efficacy at this dosage.
If severe hepatic impairment (bilirubin >3 ULN), it should not be administered.

Immunisations
Live vaccines should not be applied while taking the treatment or for at least 6 months
afterwards. Other vaccines can be administered, though may not give as much protection as
usual.
In any case, it is safe to be in contact with other people who have had live vaccines as
injections. There can be problems with oral vaccines. Any contacts with someone who has
had oral polio, cholera or typhoid vaccination recently, should be avoided.

Pregnancy
It is recommended to use effective contraception methods while on the treatment.

Breast-Feeding
It is not known if it is excreted in human milk; however, it is recommended that nursing
should be discontinued during therapy.

Warnings [1, 3, 4]

Renal Failure
Including some fatal cases. Most cases occurred in association with sepsis, dehydration,
or obstructive uropathy. Monitor and treat aggressively.

Hypersensitivity
Severe reactions can occur. Premedicate as indicated in ―M ethods of
preparation/administration‖ section. Discontinue infusion immediately if hypersensitivity is
observed and treat accordingly.
Cabazitaxel. Jevtana® 63

Diarrhoea
Mortality has been reported. Treat as needed (antidiarrhoeals and fluids) per hospital
protocol. If Grade ≥ 3 diarrhea, dosage should be modified.

Neutropenia
Neutropenic deaths have been reported. Consider primary prophylaxis with G-CSF if
high-risk.
Monitor frequently.

Toxicities [1, 3, 4]

Organic disorders Very common Common


(≥ 1/10) (>1/100 to < 1/10)
Infections and infestations Sepsis, septic shock, cellulitis, urinary tract
infections, flu, cystitis, respiratory infections,
candidiasis, shingles
Blood and lymphatic Neutropenia, anaemia,
disorders leucopenia,
thrombocytopenia, febrile
neutropenia
Hepatobiliary disorders AST elevated, transaminases elevated
Immunological disorders Hypersensitivity
Nutritional and metabolic Anorexia, taste disturbances Dehydration, hyperglycemia, hypokalemia
disorders
Nervous system disorders Peripheral neuropathy, sensitive peripheral
neuropathy, dizziness headache, paresthesia,
hypoesthesia, sciatica, ocular disturbances
Psychiatric disorders Anxiety, confusion
Cardiovascular disorders Atrial fibrillation, tachycardia, DVT,
hypertension, hypotension, orthostatic
hypotension, hot flushes, blush
Respiratory and thoracic Dyspnea, cough Oropharyngeal pain, pneumonia
disorders
Gastrointestinal disorders Nausea, vomiting, Dispepsia, hemorrhoids, gastrointestinal reflux,
constipation, abdominal rectal haemorrhage, abdominal distention
pain
Skin and hair disorders Alopecia Mouth dryness, erythema
Musculoskeletal disorders Back pain, arthralgia Pain in limbs, muscle spasms, mialgias, chest
pain
Eye and ENT disorders Conjunctivitis, increase eye lacrimation,
tinnitus, vertigo
Renal disorders Hematuria Acute renal insufficiency, disuria,
hydronephrosis, urinary incontinence, renal
colic, polaquiuria, urine retention
General disorders Fatigue, pirexia Peripheral oedema, mucositis, thoracic pain,
shivers, pelvic pain, general malaise, weight
loss
64 E. Una Cidon

Dose Modifications [1, 3, 4]

Reduce dose to 20 mg/m² with these reactions:

Toxicity Dose reduction


Febrile neutropenia Reduced dose
Prolonged neutropenia (>1 week) grade 3 Delay until neutrophil count is >1500/mm³
or greater Then restart at reduced dose consider G-CSF for secondary
prophylaxis
Persistent diarrhea or diarrhea grade 3 or Delay until recovery to grade 1 or less
greater Then restart at reduced dose
Peripheral neuropathy grade 2 Delay until improvement or resolution
Then reduce dose
Peripheral neuropathy grade 3 Stop the treatment

Interactions [1, 3, 4]

Avoid co-administration with CYP3A potent inhibitors as these will increase cabazitaxel
plasmatic concentrations. If unable to avoid it, a close surveillance and dose reduction should
be considered.
Examples: ketoconazole, itraconazole, clarithromycin, indinavir, nefazodone, nelfinavir,
ritonavir, saquinavir, telithromycin, voriconazole.
Avoid co-administration with CYP3A potent inductors as these will reduce cabazitaxel
plasmatic concentrations.
Examples: Phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, St
John's wort.

CONCLUSION
Cabazitaxel is a semisynthetic taxane which binds to tubulin and promotes microtubule
stabilization and finally inhibition of mitotic and interphase cellular functions. It has increase
the therapeutic options in patients with CRPC who are refractory to docetaxel. Its approval
was based on the TROPIC study which showed an overall median survival benefit of 2.4
months compared to mitoxantrone and with prednisone [2].
Common side effects include neutropenia and diarrhea and close monitoring to start
prompt treatment is needed [1, 3, 4]. Dose-reductions to 20 mg/m2 may often be necessary
and this dose may be considered in the future for further clinical trials [2.]

REFERENCES
[1] Cabazitaxel - Medscape Reference. http://reference.medscape.com/drug/jevtana-
cabazitaxel-999571#0.
Cabazitaxel. Jevtana® 65

[2] C.J. Paller, E.S. Antonarakis Cabazitaxel: a novel second-line treatment for metastatic
castration-resistant prostate cancer. Drug Design, Development and Therapy. 2011; 5:
117–124.
[3] Jevtana, INN-cabazitaxel - Europa. http://www.ema.europa.eu/docs/es_ES/document_
library/EPAR_-_Product_Information/human/002018/WC500104764.pdf.
[4] JEVTANA - Food and Drug Administration. http://www.accessdata.fda.gov/
drugsatfda_docs/label/2010/201023lbl. pdf.
In: The Easy Book of Cancer Pharmacology ISBN: 978-1-63485-038-4
Editor: Esther Una Cidon © 2016 Nova Science Publishers, Inc.

Chapter 8

CABOZANTINIB (XL184). COMETRIQ®

J. Molina Cerrillo, M. Gion Cortés, T. Alonso-Gordoa


and E. Grande-Pulido
Medical Oncology Department,
Ramón y Cajal University Hospital, Madrid, Spain

ABSTRACT
Tyrosine kinase inhibitors (TKI) represent a group of drugs whose mechanism of
action is related to the inhibition of tumor growth, angiogenesis and metastatic
progression of cancer cells.
Cabozantinib, initially identified as XL184 (Exelixis), was developed as a novel TKI
against VEGFR (vascular endothelial growth factor receptor), MET (hepatocyte growth
factor receptor) and RET (rearranged during transfection) as well as other targets
including AXL (GAS6 receptor) c-Kit and FLT3 (fms-like tyrosine kinase 3). In fact, the
potent mechanism of action and initial clinical findings led to the research of its particular
activity in different tumor types.
Cabozantinib has been recently approved for the treatment of patients with advanced
and progressive medullary thyroid carcinoma (MTC). A multi-center, randomized,
placebo-controlled, phase III trial (EXAM trial) compared cabozantinib vs placebo in
patients with unresectable locally advanced or metastatic MTC and documented
radiographic disease progression. The trial showed a significant benefit in the primary
endpoint, the progression free survival (PFS) in the cabozantinib group vs the placebo
group [median PFS 11.2 vs 4.0 (HR: 0.28, p < 0.0001) and 1 year PFS rate 47.3% vs
7.2%].
Frequent adverse events include fatigue, nausea, diarrhea, hand-foot syndrome,
hypertension, mucositis and decreased in weight and appetite.

Keywords: cabozantinib, tyrosine kinase inhibitor


Email: egrande@oncologiahrc.com.
68 J. Molina Cerrillo, M. Gion Cortes, T. Alonso-Gordoa et al.

INTRODUCTION
Cabozantinib is a TKI with antitumor activity demonstrated in preclinical research with
murine xenograft tumor models and in different solid tumors cell lines. Cabozantinib inhibits
multiple targets including RET, VEGFR and MET tyrosine kinase receptors [1-6].
In a phase I trial that included 37 patients with medullary thyroid cancer (MTC),
cabozantinib showed promising results with a safety profile [7]. In the EXAM trial, 330
patients with MTC were randomized in a 2:1 ratio to cabozantinib 140-mg/day vs placebo.
The primary endpoint was PFS and crossover was not allowed. This study demonstrated the
efficacy of cabozantinib in terms of PFS: 11.2 months vs 4 months, HR 0.28. Median overall
survival (OS) was 26.0 months in the cabozantinib group vs 20.3 months in the placebo group
although no statistical significance was met [8].
Cabozantinib has shown preliminar activity in other solid tumor types including prostate
cancer, hepatocelullar carcinoma, renal cell carcinoma among others [9, 10, 12-16].
The most frequent adverse effects found with the use of cabozantinib are diarrhea,
fatigue, decrease appetite and weight, nausea, palmar and plantar erythrodysesthesia (PPE),
rash and increased transaminases [5, 12, 17].

DRUG CLASSIFICATION
Small molecule TKI [18].

MECHANISM OF ACTION
Cabozantinib binds with high affinity to multiple tyrosine kinases that are involved in
tumor cell growth and survival, angiogenesis and metastatic progression. Cabozantinib is a
potent inhibitor of RET, VEGFR and MET. RET is a proto-oncogen located on epithelial
derived cells and activates multiple signaling pathways that promote survival, proliferation,
differentiation and motility. VEGFR is involved in angiogenesis regulation that is required for
tumor progression and MET that is involved in cell-to-cell adhesion and motility, that implies
an aggressive phenotype to the tumor. Recent findings suggest that the inhibition of VEGFR
pathways may lead to upregulation of other routes like MET, therefore cabozantinib is able to
inhibit this escape pathway of the angiogenesis achieving a higher control in tumor
angiogenesis [3, 4, 6, 19, 20].

PHARMACOKINETICS [17, 18]


Absorption Oral administration. Peak plasma concentration is reached at 2 to 5 hours post-dose. Steady state
is achieved at, approximately, day +15. Maximum concentration is caused by high-fat meal
Distribution High protein bound in vitro in human plasma (≥99,7%)
Metabolism Hepatic metabolism (CYP3A4-mediated)
Median plasma half-life: 120h
Excretion Mainly GIand urinary excretion.
Cabozantinib (XL184). Cometriq® 69

MECHANISM OF RESISTANCE
No information is currently available about the mechanisms of resistance of cabozantinib
but it is believed that increase of the production and release of other proangiogenic factors
different than VEGF may be involved together with activation of protumoral intracellular
pathways.

INDICATIONS
Cabozantinib has been approved for the treatment of adult patients with progressive,
unresectable locally advanced or metastatic MTC. In the phase III EXAM trial, this drug
reached a benefit in PFS of nearly 8 months over placebo. In the subgroups analyses, there
were no differences in terms of activity between naïve and previously treated patients.
Moreover, the benefit from the use of cabozantinib was also observed across multiple
sensitivity and subgroup analyses, including the presence of bone metastases, and in all RET
mutation subgroups analyzed [8].

DOSAGES
The recommended dose is 140 mg once daily (one 80 mg orange capsule and three 20 mg
grey capsules. If it is necessary a dose reduction, it is recommended to reduce to 10mg daily
(one 80 mg orange capsule and one 20 mg grey capsule) and the 60 mg daily (three 20 mg
grey capsules) [12, 17, 18].
A phase IV trial is currently ongoing to evaluate the efficacy and safety of two different
doses (60 mg and 140 mg once daily) [8].

METHODS OF PREPARATION/ADMINISTRATION
Cabozantinib must be taken on an empty stomach and patients should avoid eating at
least 1 hour before or 2 hours after the drug administration.
Patients should avoid concurrent intake of grapefruit or grapefruit juice (cabozantinib
serum concentration may increase). A high-fat meal increased C.max and AUC (area under
curve) by 41% and 57%, respectively compared to the fasted state [17, 18].

SPECIAL INFORMATION AND CAUTIONS [17, 18]


Contraindications

Hypersensitivity to the substance or to the excipients listed below:


70 J. Molina Cerrillo, M. Gion Cortes, T. Alonso-Gordoa et al.

 Capsule content:
Microcrystalline cellulose
Croscarmellose sodium
Sodium starch glycolate
Silica colloidal anhydrous
Stearic acid

 Capsule shell:
Gelatin
Black iron oxide (E172)
Titanium dioxide (E171)

 Printing ink:
Shellac
Black iron oxide (E172)
Propylene glycol

Elderly Patients

No specific dose adjustment in initial dose for the use of cabozantinib in older people
(≥65 years) is recommended. However, in patients aged 75 and older have shown a trend in
increased risk of adverse events.

Pediatric Patients

The safety and efficacy of cabozantinib in children aged < 18 years have not yet been
established. No data are available.

Renal Impairment

There are limited data in this patient population. Cabozantinib should be used with
caution in patients with renal impairment and it is not recommended in patients with severe
renal impairment.

Hepatic Impairment

There are limited data in patients with hepatic impairment, and safety and efficacy have
not been clearly established. Hence, cabozantinib is not recommended in patients with hepatic
impairment.
Cabozantinib (XL184). Cometriq® 71

Pregnancy and Breast Feeding

Based on its mechanism of action, adverse effects on pregnancy would be expected.


Patients (males and females) should use effective contraception during therapy and for up to 4
months after therapy completion.
Excretion in breast milk is unknown.

Immunizations

Live vaccines should not be applied while taking the treatment or for at least 6 months
afterwards. Other vaccines can be administered, though may not give as much protection as
usual.
In any case, it is safe to be in contact with other people who have had live vaccines as
injections. There can be problems with oral vaccines. Any contacts with someone who has
had oral polio, cholera or typhoid vaccination recently, should be avoided.

WARNINGS [17, 18]


Haemorrhage

Cabozantinib should not be administered to patients with serious haemorrhage or recent


haemoptysis.

Hypertension

Cabozantinib should be discontinued if hypertension is severe and persistent despite anti-


hypertensive therapy and dose reduction of cabozantinib or in case of hypertensive crisis.

Osteonecrosis

An oral examination should be performed prior to initiation of cabozantinib and


periodically during therapy. Cabozantinib should be discontinued in patients who experience
osteonecrosis.

Palmar-Plantar Erythrodysaesthesia Syndrome (PPES)

If PPES is ≥ grade 3, interruption of treatment with cabozantinib should be considered.


Cabozantinib should be restarted with a lower dose when PPES has been resolved to grade 1.
72 J. Molina Cerrillo, M. Gion Cortes, T. Alonso-Gordoa et al.

Perforations, Fistulas, and Intra-Abdominal Abscesses

Serious GI perforations and fistulas, sometimes fatal, and intra-abdominal abscesses,


have been observed with cabozantinib.

Prolongation of QT Interval

Cabozantinib should be used with caution in patients with a history of QT interval


prolongation, patients who are taking antiarrhythmics, or patients with relevant pre-existing
cardiac disease, bradycardia, or electrolyte disturbances.

Proteinuria

Cabozantinib should be discontinued in patients who develop nephrotic syndrome.

Proton Pump Inhibitors

The effect of proton pump inhibitors on the GI absorption of cabozantinib has not been
determined. The concomitant use with this therapeutic class is, therefore, not recommended.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS)

Cabozantinib should be discontinued in patients who develop RPLS.

Thromboembolic Events

Cabozantinib should be used with caution in patients who are at risk for these events and
it should be discontinued in patients who develop an acute myocardial infarction or any other
clinically significant arterial thromboembolic complication.

Wound Complications

Cabozantinib should be discontinued in patients with wound healing complications


requiring medical intervention.
Cabozantinib (XL184). Cometriq® 73

TOXICITIES [17, 18]


Disorders Very common (≥1/10) Common (≥1/100 to uncommon
<1/10) (≥1/1,000 to <1/100)
Cardiovascular Hypertension Venus and arterial Ventricular
thromboembolism, atrial fibrillation
fibrillation
Central Fatigue, headache, dizziness Paraesthesia, ageusia Ataxia, Reversible
nervous system posterior
leukoencephalopathy
syndrome
Dermatologic Palmar-plantar Hyperkeratosis, skin skin ulcer,
erythrodysesthesia, hair color hypopigmentation telangiectasia
changes, dry skin, rash, alopecia,
erythema
Ear disorders Ear pain, tinnitus Hypoacusia
Endocrine Hypocalcemia, Hyponatremia,
hypophosphatemia, dehydration,
hypomagnesemia, hypokalemia hypothyroidism
Eye disorders Vision blurred cataract,
conjunctivitis
GI Diarrhea, stomatitis, weight loss, GI perforation, GI GI fistula,
appetite decreased, nausea, oral haemorrhage, pancreatitis, oesophagitis
pain, abnormal taste, abdominal haemorrhoids, anal fissure,
pain, constipation, vomiting, anal inflammation,
dysphagia, dyspepsia cheilitis
Hematologic Lymphopenia, neutropenia, Haemorrhage
thrombocytopenia
Hepatic ALT increased, AST increased, Cholelithiasis
alkaline phosphatase increased,
hyperbilirubinemia
Neuromuscular Weakness, arthralgia, muscle Musculoskeletal chest Osteonecrosis of the
and skeletal spasms pain, paresthesia, jaw, rhabdomyolysis
peripheral neuropathy
Renal Proteinuria, dysuria, Acute renal failure
haematuria
Reproductive Amenorrhoea,
system vaginal haemorrhage

DOSE MODIFICATIONS [ACCORDING TO COMMON TERMINOLOGY


CRITERIA FOR ADVERSE EVENTS (CTCAE)] [17, 18]
Hematologic Toxicities

Cabozantinib should be stopped when grade 3-4 hematologic adverse reaction occurs.
Once toxicity returns to baseline or improves to grade 1, cabozantinib can be reintroduced,
but at a lower dose (100 mg daily).
If previously receiving 100 mg daily, therapy should be resumed at 60 mg daily dose.
If previously receiving 60 mg daily, resume at 60 mg daily if tolerated. Otherwise,
therapy should be discontinued.
74 J. Molina Cerrillo, M. Gion Cortes, T. Alonso-Gordoa et al.

Other Non-Hematologic Toxicities

Treatment should be temporarily interrupted if grade  3 toxicity or intolerable grade 2


toxicity occurs. Once toxicity returns to baseline or improves to grade 1, therapy can be
reintroduced, but at a lower dose (100 mg daily).
If previously receiving 100 mg daily, therapy should be resumed at 60 mg daily dose.
If previously receiving 60 mg daily, resume at 60 mg daily if tolerated. Otherwise,
therapy should be discontinued.

Permanent Discontinuation

Cabozantinib should be permanently interrupted in the following situations:

 Visceral perforation or fistula.


 Nephrotic syndrome.
 Malignant hypertension.
 Reversible posterior leukoencephalopathy syndrome.
 Serious arterial thromboembolic event.
 Severe hemorrhage.

INTERACTIONS [4, 17, 18]


Strong CYP3A4 Inducers

These drugs may decrease the serum concentration of cabozantinib.


Avoid concomitant use. If concomitant use is required, increase the daily dose by 40 mg.

Strong CYP3A4 Inhibitors

These drugs may increase the serum concentration of cabozantinib.


Avoid concomitant use. If concomitant use is required, reduce the daily dose of
cabozantinib by 40 mg.

Bisphosphonates

Cabozantinib may enhance the adverse/toxic effect of bisphosphonates. The risk for
osteonecrosis of the jaw may be increased.
Cabozantinib (XL184). Cometriq® 75

Serum concentration of cabozantinib


Increase Decrease
Ceritinib Dabrafenib
Palbociclib Dexamethasone
Dasatinib
Aprepitant, Fosaprepitant, Netupitant

CONCLUSION
Cabozantinib is an orally available TKI against RET, MET and VEGFR, that are
involved in many oncological steps. Its activity has been demonstrated in a phase III clinical
trial including patients with MTC, but other clinical trials with cabozantinib are currently
ongoing in other tumors due to its potent antitumoral activity. On the other hand, its potential
serious adverse events require a close monitoring by expert physicians.
Further studies are required to achieve a better understanding of the pathways involved in
cancer development and progression and the effect of cabozantinib on it, particularly the
mechanisms of resistance.

REFERENCES
[1] Targeting cancer with small molecule kinase inhibitors. Zhang J, Yang PL, Gray NS.
Nat Rev Cancer. 2009;9(1):28.
[2] Cui, JJ. Inhibitors targeting hepatocyte growth factor receptor and their potential
therapeutic applications. Expert Opin Ther Pat. 2007; 17:1035.
[3] Grüllich C. Cabozantinib: a MET, RET, and VEGFR2 tyrosine kinase inhibitor. Recent
Results Cancer Res. 2014;201:207-14.
[4] Roy S, Narang BK, Rastogi SK, Rawal RK. A novel multiple tyrosine-kinase targeted
agent to explore the future perspectives of anti-angiogenic therapy for the treatment of
multiple solid tumors: Cabozantinib. Anticancer Agents Med Chem. 2014;15(1):37-47.
[5] Hoy SM. Cabozantinib: a review of its use in patients with medullary thyroid cancer.
Drugs. 2014 Aug;74(12):1435-44.
[6] Vaishampayan UN. Development of cabozantinib for the treatment of prostate cancer.
Core Evid. 2014 Apr 23;9:61-7.
[7] Kurzrock R, Sherma SI, Ball DW, et al. Activity of XL184 (cabozantinib), an oral
tyrosine kinase inhibitor, in patients with medullary thyroid cancer. J Clin Oncol.
2011;29(19):2660–2666.
[8] Schoffski P, Elisei R, Muller S, et al. An international, double-blind, randomized,
placebo-controlled phase III trial (EXAM) of cabozantinib (XL184) in medullary
thyroid carcinoma (MTC) patients (pts) with documented RECIST progression at
baseline. J Clin Oncol 2012; 30 (suppl):5508.
[9] Hussain, M., Smith, M., Sweeney, C., Corn, P., Elfiky, A., Gordon, M., et al.
Cabozantinib (XL184) in metastatic castration resistant prostate cancer (mCRPC):
76 J. Molina Cerrillo, M. Gion Cortes, T. Alonso-Gordoa et al.

Results from a Phase 2 randomized discontinuation trial. J. Clin. Oncol., 2011, 29, 1-
29.
[10] Smith MR, De Bono JS, Sternberg CN, Moulec SL, Oudard S, Giorgi UD. Final
analysis of COMET-1: Cabozantinib (Cabo) versus prednisone (Pred) in metastatic
castration-resistant prostate cancer (mCRPC) patients (pts) previously treated with
docetaxel (D) and abiraterone (A) and/or enzalutamide (E). J Clin Oncol 33, 2015
(suppl 7; abstr 139).
[11] Basch EM, Scholz MC, De Bono JS, Vogelzang NJ, De Souza PL, Marx GM. Final
analysis of COMET-2: Cabozantinib (Cabo) versus mitoxantrone/prednisone (MP) in
metastatic castration-resistant prostate cancer (mCRPC) patients (pts) with moderate to
severe pain who were previously treated with docetaxel (D) and abiraterone (A) and/or
enzalutamide (E). J Clin Oncol 33, 2015 (suppl 7; abstr 141).
[12] Choueiri TK, Pal SK, McDermott DF, Morrissey S, Ferguson KC, Holland J et al. A
phase I study of cabozantinib (XL184) in patients with renal cell cancer. Ann Oncol.
2014 Aug;25(8):1603-8.
[13] Gordon, M., Vogelzang, N., Schoffski, P., Daud, A., Spira, A., O'Keeffe, B., Rafferty,
T., Lee, Y., Berger, R., Shapiro, G. Activity of cabozantinib (XL184) in soft tissue and
bone: Results of a phase II randomized discontinuation trial (RDT) in patients (pts) with
advanced solid tumors. J. Clin. Oncol., 2011, 29, 196.
[14] Bergsland, E. K. In The evolving landscape of neuroendocrine tumors, Seminars in
oncology, 2013; Elsevier: 2013; pp 4-22.
[15] Verslype, C., Cohn, A. L., Kelley, R. K., Yang, T. S., Su, W. C., Ramies, D. A., et al.
Activity of cabozantinib (XL184) in hepatocellular carcinoma: Results from a phase II
randomized discontinuation trial (RDT). J. Clin. Oncol., 2012, 30, 4007.
[16] Hellerstedt, B. A., Edelman, G., Vogelzang, N.J., Kluger, H.M., Yasenchak, C. A.,
Shen, et al. Activity of cabozantinib (XL184) in metastatic NSCLC: Results from a
Phase 2 randomized discontinuation trial (RDT). Cancer (NSCLC), 2012, 6, 7.
[17] FDA. Available at: www.accessdata.fda.gov/drugsatfda_docs/label/2012/203756lbl.pdf.
[18] EMA information. Available at: http://www.ema.europa.eu/docs/en_GB/document_
library/EPAR_-_Product_Information/human/002640/WC500163703.pdf.
[19] Yakes, F. M, Chen, J, Tan, J, Yamaguchi, K, Shi, Y, Yu, P, Qian, F, Chu, F, Bentzien,
F, Cancilla, B. Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor
simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol. Cancer
Ther., 2011, 10, 2298-2308.
[20] Marsh DJ, Learoyd DL, Andrew SD, et al. Somatic mutations in the RET proto-
oncogene in sporadic medullary thyroid carcinoma. Clin Endocrinol (Oxf).
1996;44(3):249–257.
In: The Easy Book of Cancer Pharmacology ISBN: 978-1-63485-038-4
Editor: Esther Una Cidon © 2016 Nova Science Publishers, Inc.

Chapter 9

CAPECITABINA. XELODA®

P. Diezhandino and P. Alonso


Radiotherapy Oncology Service, Clinical Universitary Hospital,
Valladolid, Spain

ABSTRACT
Antimetabolites agents are folic acid, pyrimidineorpurine analogues, characterized
bylow molecular weights. They are chemotherapeutic drugs with similar structures as
natural molecules used in nucleicacid (DNA and RNA) synthesis. Fluoropyrimidines are
antimetabolite agents and capecitabine is a new oral fluoropyrimidine developed in order
to facilitate its administration. This drug was developed as a prodrug of 5-fluorouracil (5-
FU), with the goal of improving tolerability and intratumor drug concentrations through
tumor-specific conversion to the active drug. Capecitabine is activated in the tumor cell
and converted to its only active metabolite, 5-FU, by thymidinephosphorylase. It is
administered orally and absorbed by intestinal cells. The most common dose-limiting
adverse effects are hyperbilirubinemia, diarrhea, and hand-footsyndrome.

Keywords: capecitabine, fluoropyrimidine

INTRODUCTION
Capecitabine is an oral fluoropyrimidine which is activated in the tumor cell and
converted to its only active metabolite 5-FU by thymidine phosphrylase. Higherlevels of
thisenzyme are found in several tumors and theliver, compared with normal healthy tissue.
Capecitabine was developed with the goal of improving tolerability and increase intratumor
drug concentrations. Although it can produce myelosuppression, fatigue, weakness,
abdominal pain and nausea, its most relevant side-effects are diarrhoea, hand-foot syndrome
and hyperbilirubinemia [1].


Patricia Diezhandino, pdg22@hotmail.es.
78 P. Diezhandino and P. Alonso

CLINICAL PHARMACOLOGY
Drug Classification

It is an oral fluoropyrimidine (antimetabolite).

Mechanism of Action

Capecitabine is a fluoropyrimidine carbamate. The activation to cytotoxic forms is a


complex process that involves three consecutive enzimatic steps. It is metabolized in the liver
to 5´-deoxy-5-fluorocytidine (5´-DFCR) by the carboxylesterase enzyme and then to 5´-
deosy-5-fluorouridine (5´- DFUR) by cytidine deaminase (in liver and in tumor tissues).
Subsequently converted to 5-FU by thymidine phosphorylase (ThyPasa), enzyme which is
found mainly in tumor cells and less in normal tissues [2]. Capecitabine antitumor activity is
enhanced if ThyPasa concentrations increase in tumor cells, which has been achieved in
xenografts of human breast and colon after prior exposure to various cytotoxic agents as
taxanes, mitomycin C, cisplatin, cyclophosphamide, vinca alkaloid, gemcitabine, and
radiotherapy [3, 4] resulting in a synergistic activity.

PHARMACOKINETICS
Absorption Peak blood levels in 1.5 hours (Tmax) with peak 5-FU levels at 2 hours.
Food reduced the rate and extent of absorption of capecitabine and 5-FU. It reduced
Tmax by 1.5 hours.
Distribution Plasma protein binding is less than 60% (primarily bound to albumin, approximately
35%). This is not concentration-dependent.
Metabolism Extensively metabolized to 5-FU.
Dihydropyrimidine dehydrogenase hydrogenates 5-FU to the much less toxic 5-fluoro-5,
6-dihydro-fluorouracil (FUH2).
Mainly in liver.
Excretion Mainly in urine is 96%. Major metabolite excreted by urine (57%) is alfa-fluoro-beta-
alanine (FBAL) and 3% is excreted unchanged.
3% is fecal elimination.
The elimination half-life is 30 to 60 minutes.

Mechanism of Resistance

Mechanisms of resistance include alterations in the kinetics of ThyPasa, depletion of


folatecofactors, orthelevel of thecompetingsubstrate, deoxyuridine monophosphate (dUMP)
[1].
Capecitabina. Xeloda® 79

Indications

Single-agent adjuvant treatment for Dukes' stage C colonorrectum cancer patients who
have undergone complete resection of theprimary tumor in those instances when
fluoropyrimidine therapy alone would be preferred.

 Metastatic colorectal cancer.


 Metastatic breast cancer.

Off-label uses:

 Gastriccancer
 Esophageal cancer
 Hepatobiliary cancer
 Neuroendocrine tumors
 Ovarian, fallopian tuve o peritoneal cancer
 Pancreatic tumor
 Anal carcinoma
 Unknown primary cancer (head and Neck cancer)

METHODS OF PREPARATION/ADMINISTRATION
It is given as a tablet by mouth. The tablet should be swallowed with water within 30
minutes after a meal.
There are tablets of 500mg and 150mg.

Dosage

In monotherapy or in combination with docetaxel


-1250mg/m2/12 hours, 14 days, followed by 1 week off.
In combination with cisplatin: 800-1000 mg/m2/2 times a day, 14 days, followed by 1
week off; or 625mg/m2/2 times daily continuously.
In combination with oxaliplatin: 1000 mg/m2every three weeks.

SPECIAL INFORMATION AND CAUTIONS [5]


Contraindications

Known hypersensitivity to 5-FU or known deficiency of dihydropyrimidine


dehydrogenase (DPD) deficiency or severe renal impairment (creatinine clearance below 30
mls/min).
80 P. Diezhandino and P. Alonso

It is also contraindicated if known hypersensitivity to any of the excipients listed below:


Tablet core

Anhydrous lactose
Croscarmellose sodium
Methylcellulose
Microcrystalline cellulose
Magnesium stearate
Tablet coating

Methylcellulose
Titanium dioxide (E171)
Oxide yellow and red iron (E172)
Talcum powder

Elderly Patients

Caution should be applied at the time of prescribing this drug to elderly patients. It has
been described that patients older than 80 may develop higher incidence of side-effects grade
3-4.

Pediatric Patients

Safety and effectiveness has not been established.

Renal Impairment

Mild and moderate renal impairment require close monitoring.


Moderate renal impairment (CrCL 30-50ml/min) requires dose reduction (use 75% of the
dose).
Severe renal impairment (CrCL < 30ml/min): the use of capecitabine is not indicated.
Prompt interruption and dose adjustment is required if toxicity grade 2-4.

Liver Impairment

Mild to moderate should be closely monitored for toxicities.


Severe liver impairment has not been studied.
Capecitabina. Xeloda® 81

Immunisations

Live vaccines should not be applied while taking the treatment or for at least 6 months
afterwards. Other vaccines can be administered, though may not give as much protection as
usual. In any case, it is safe to be in contact with other people who have had live vaccines as
injections. There can be problems with oral vaccines. Any contacts with someone who has
had oral polio, cholera or typhoid vaccination recently, should be avoided.

Pregnancy

Adverse effects were observed in animal reproduction studies. Fetal harm may occur if
administered during pregnancy. A contraceptive method is recommended.

Lactation

It is not recommended.

Warnings

DPD Deficiency

Patientes who experience unexpected, sever grade3 or 4 myelosupression, gastrointestinal


toxicity, and or neurologic toxicity upon initiation of therapy may have an underlying
deficiency in DPD. Therapy must be discontinued immediately and further testing to identify
the presence of this pharmacogenetic síndrome should be considered.

Toxicities [6]
Organic disorders Very Common (≥1/100 a <1/10) Uncommon
common (≥1/1.000 a <1/100)
(≥1/10)
Cardiac toxicity Unstable angina, angina pectoris,
myocardial ischemia, atrial fibrillation,
arrhythmia, sinus tachycardia, palpitations
Disorders of the Anemia, neutropenia. Febrile neutropenia, pancytopenia,
blood and thrombocytopenia, leukopenia, hemolytic
lymphatic system anemia, increased international normalized
ratio (INR)/Prothrombin time prolonged
Infections and Herpes infection, lower Sepsis, urinary tract infection, cellulitis,
infestations respiratory tract infection, tonsillitis, pharyngitis, oral candidiasis,
nasopharyngitis influenza, gastroenteritis, fungal infection,
dental abscesses
82 P. Diezhandino and P. Alonso

(Continued)

Organic disorders Very Common (≥1/100 a <1/10) Uncommon


common (≥1/1.000 a <1/100)
(≥1/10)
Psychiatric Insomnia, depression Confusional state, panic attacks, depressed
disorders mood, decreased libido
Nervous system Headache, lethargy, Aphasia, memory impairment, ataxia,
disorders dizziness, paraesthesia, syncope, balance disorder, sensory
dysgeusia disorders, peripheral neuropathy
Eye and Lacrimation increased, Reduced visual acuity, dyplopia vertigo,
eardisorders conjunctivitis, eye irritation earache
Gastrointestinal Diarrhea, Gastrointestinal bleeding, Bowel obstruction,
disorders vomiting, constipation, pain in the ascites, enteritis, gastritis, dysphagia, pain in
nausea, upper tract of the abdomen, the lower abdominal tract, esophagitis,
stomatitis, dyspepsia, flatulence, dry abdominal discomfort, gastroesophageal
abdominal mouth reflux disease, colitis, blood in stool.
pain

Organic Very Common (≥1/100 a <1/10) Uncommon


disorders common (≥1/1.000 a <1/100)
(≥1/10)
Skin and Palmoplanta Rash, alopecia, erythema, Skin ulcers, rash, urticaria, photosensitivity
subcutaneous r dry skin, pruritus, skin reaction, palmar erythema, swelling of the
tissue disorders erythrodyse hyperpigmentation, macular face
s-thesia rash, skin peeling,
syndrome dermatitis, abnormal
pigmentation
Metabolism, Anorexia Dehydration, decreased Diabetes, hypokalaemia, appetite disorder,
nutrition and appetite, weight decreased malnutrition, hypertriglyceridemia
endocrine disorder
Vascular disorder Thrombophlebitis Deep vein thrombosis, hypertension,
petechiae, hypotension, flushing with heat
sensation, feeling cold peripheral
Musculoskeletal Extremity pain, back pain, Joint swelling, pain
and connective arthralgia bones, facial pain, Musculoskeletal stiffness,
tissue disorders Muscular weakness
Renal and urinary Hydronephrosis, urinary incontinence,
disorders haematuria, nocturia, increased blood
creatinine
Hepatobiliary Hyperbilirubinemia, Jaundice
disorders alterations in liver function
tests
General disorders Fatigue, Pyrexia, lethargy, edema Edema, chills, flu syndrome, stiffness,
and administration asthenia peripheral, Chest pain increased body temperature
site
Reproductive vaginal bleeding
system and breast
Capecitabina. Xeloda® 83

Note

Hand-foot Syndrome (palmar-plantar erythrodysesthesia): characterized by tingling,


numbness, pain, erythema, dryness, rash, swelling, increased pigmentation, nail changes,
pruritus of the hands and feet, and/or desquamation. Vitamin B6 (pyridoxine, 50mg PO bid)
and Celecoxib (200mg PO bid) may be used to prevent and/or reduce the incidence and
severity of this toxicity.

Dose Modification [5]

Grade 1 Toxicities
No dose modification is recommended.

Grade 2
Drug therapy should be stopped immediately until complete resolution or back to
intensity grade 1 or less.
Then treatment should continue at the same dose if first appearance or with a reduction of
25% if second appearance.

Grade 3
Drug therapy should be stopped immediately until complete resolution or back to
intensity grade 1 or less. Then treatment should continueat 75% of the initial starting dose if
first appearance or 50% if second appearance.

Grade 4
Drug therapy should be stopped immediatelyuntil complete resolution or back to intensity
grade 1 or less.
Then if the physician chooses to continue this treatment as it is in best patient´s interest,
dose could continue at 50%.

NOTE

Drug therapy should be stopped immediately in the presence of grades 2 to 4


hyperbilirubinemia until complete resolution or a decrease in intensity to grade 1.
Doses of capecitabine omitted due to toxicity are not resumed.

Interactions [6]

Drug Mechanism
Warfarine Altered coagulation parameters (Prothrombin time and INR) and bleeding
Phenytoin Capecitabine may increase phenytoin blood levels and toxicity.
Leucovorin It enhances the antitumor activity and toxicity of capecitabine
Sorivudineand Brivudine Do not administer together. Wait 4 weeks
84 P. Diezhandino and P. Alonso

(Continued)

Drug Mechanism
Aluminum hydroxide, Increased plasma concentrations of capecitabine and metabolite (5´-
magnesium hydroxide DFCR)
Allopurinol Reduced efficacy of 5-FU. Avoid concomitant use of allopurinol with
capecitabine.

CONCLUSION
Xeloda is the first drug in a new class of fluoropyrimidines that offers advantages over its
predecessor, the 5-FU. On the one hand, oral administration, which improves compliance by
patients and avoids the complications and costs of intravenous route; and secondly, the
selective activation by tumor enhances antitumor activity and lowers systemic toxicity.
Side-effects most commonly reported and/or clinically relevant were gastrointestinal
disorders (especially diarrhea), palmar-plantar erythrodysesthesia, fatigue, asthenia, anorexia,
cardiotoxicity, increased renal failure in patients with compromised renal function prior and
thrombosis/embolism. The frequency of hand-foot syndrome varies according to the dose
received. The adverse event profile of capecitabine [7] is similar to the 5-FU bolus
administered, but the incidence of diarrhea, stomatitis, nausea and alopecia is less.
The wide spectrum of antitumor activity makes this drug an excellent treatment option
with good tolerability and safety profile.

REFERENCES
[1] Malet-Martino M, Martino R. Clinical studies of three oral prodrugs of 5-fluorouracil
(Capecitabine, UFT, S-1): a review. The Oncologist. 2002; 7: 288-323.
[2] Capecitabine. In: Chu Edward, DeVita Vincent T Jr. Eds. Physicians´ Cancer
Chemotherapy Drug Manual 2015. Jones and Barlett Publishers; 2015.p. 82-3.
[3] Sawada N, Ishikawa T, Fukase Y, Nishida M, Yoshikubo T, Ishituka H. Induction of
thymidine phosphorylase activity and enhancement of capecitabine efficacy by
Taxol/Taxotere in human cancer xenografts. Clin. Cancer Res. 1998; 4: 1013-9.
[4] Sawada N, Ishikawa T, Sekiguchi F, Tanaka Y, Ishitsuka H. X-rayirradiation induces
thymidinephosphorylase and enhancestheefficacy of capecitabine (Xeloda) in human
cancerxenografts. Clin. Cancer Res. 1999; 5: 2948-53.
[5] Capecitabine. In: Chu Edward, DeVita Vincent T Jr. Eds. Physicians´ Cancer
Chemotherapy Drug Manual 2015. Jones and Barlett Publishers; 2015.p. 85-6.
[6] Fichatécnica Xeloda® (capecitabina) disponibleen: http://www.ema. europa.eu/ema/
index.jsp?curl=pages/medicines/human/medicines/000316/human_med_001157.jsp&m
id=WC0b01ac058001d124&jsenabled=true Fichatécnica.
[7] Capecitabina (Xeloda®) para el tratamiento de primera línea del cáncer
colorrectalmetastático y como adyuvante a la cirugía radical en el cáncer colorrectal en
estadio III. Hospital Valld‘Hebrón. Servei de Farmacología Clínica (Julio 2005).
In: The Easy Book of Cancer Pharmacology ISBN: 978-1-63485-038-4
Editor: Esther Una Cidon © 2016 Nova Science Publishers, Inc.

Chapter 10

CARBOPLATIN. PARAPLATIN®. CBDCA.


DIAMMINEPLATINUM (II).
CIS-(1,1.CYCLOBUTANEDICARBOXYLATO).
CIS-DIAMMINE
(1,1-CYCLOBUTANEDIOCARBOXYLATO) PLATINUM

M. Luque Cabal1, and P. Garcia Teijido2


1
Medical Oncology Department,
University Hospital of Asturias, Oviedo, Spain
2
Medical Oncology Department,
―San Ag ustin‖ Hospital, Aviles, Spain

ABSTRACT
Carboplatin is an analog of cisplatin and it has the same range of clinical activity. Its
lower reactivity with nucleophilic sites of DNA may be related to the higher dose
necessary to obtain an antitumor effect similar to that of cisplatin. Carboplatin has
replaced cisplatin in the treatment of ovarian cancer and it is frequently used in other
malignancies as lung cancer. It is no necessary to administrate pre-treatment hydration
with intravenous fluids and its infusion time can be 30 minutes or less. The systemic drug
exposure produced by any dose in a patient can be reasonably estimated on the basis of
his or her renal function, so dosing given in area under the drug exposure curve (AUC) is
associated with more predictable myelosuppression. It is more toxic to bone marrow than
cisplatin, but it causes less nephrotoxicity, emesis and neurotoxicity.

Keywords: carboplatin, platin, CBDCA


Email: malucabal@yahoo.es.
86 M. Luque Cabal and P. Garcia Teijido

INTRODUCTION
Carboplatin (cis-diammine(1,1-cyclobutanedicarboxylato)platinum(II)), an analog of
cisplatin, was introduced into clinical trials in 1981 to help circumvent some of the toxicities
of cisplatin. It differs from cisplatin by its cyclobutanedicarboxylate group at the position of
the 2 chlorides in cisplatin [1]. Carboplatin has replaced cisplatin in chemotherapy regimens
of some diseases, such as ovarian carcinoma, but cisplatin is superior in efficacy across other
tumors like bladder, lung, head and neck, esophagus, germ cell or pancreas carcinomas [2].

CLINICAL PHARMACOLOGY
Drug Classification

Mechanism of Action
Carboplatin is a platinum derivate and it shares the same mechanism of action as
cisplatin. It is formed by replacing the chloride leaving groups of cisplatin with 1,1-
cyclobutanedicarboxylato ligand, which increases the stability of the leaving groups. Its
cytotoxic activity is similar to cisplatin as it binds with DNA to form intra-strand crosslinks
and adducts that cause changes in the conformation of the DNA and affect DNA replication.
In vitro, carboplatin induces the same platinum-DNA adducts as those induced by cisplatin,
but carboplatin requires a 10 times higher drug concentration and 7.5 times longer incubation
time than cisplatin to induce the same degree of conformational change on plasmid DNA [3].

PHARMACOKINETICS [4, 5]
Absortion Not applicable if intravenous (iv) administration.
Intraperitoneal: 65% after a 4 hour dwell period.
Distribution Widely distributed in body tissues. Crosses the blood-brain barrier and enters the CSF.
Carboplatin does not bind to plasma proteins and it has a volume of distribution of
approximately 16 L.
Metabolism Carboplatin is transformed under an aquation reaction in the presence of low
concentrations of chloride.
The dicarboxilate ligand slows the metabolic breakdown of carboplatin. This reaction is
100-fold slower with carboplatin when compared to cisplatin [6].
Excretion The main route of elimination is renal excretion. Patients with creatinine clearances of
60 mL/min or greater excrete 65% of the dose within 24 hours, as carboplatin. Only 3%
to 5% of the administered carboplatin is excreted in the urine between 24 and 96 hours.
There are not enough data about biliary excretion. In patients with creatinine clearances
under 60 mL/min, the body and renal clearances of carboplatin decrease. The primary
determinant of carboplatin clearance is glomerular filtration rate (GFR), so dosing
formulas incorporating this parameter should be used in elderly patients and in those
with renal disorders.
Carboplatin. Paraplatin®. CBDCA. 87

Mechanism of Resistance

Cellular resistance to carboplatin is less well studied. Because carboplatin and cisplatin
share a similar structure, undergo hydrolytic reaction leading to the same active intermediates,
lead to the same DNA lesions, and are cross-resistant in most instances, it is assumed that
similar mechanisms are involved in carboplatin resistance.

Indications [4]

1. Ovarian cancer
2. Other uses:
i. Brain tumors
ii. Breast cancer
iii. Neuroendocrine Tumors
iv. Bladder cancer
v. Endometrial, fallopian tube, primary peritoneal cancer
vi. Lung cancer: small cell, non-small cell
vii. Testicular cancer
viii. Cancer of unknown primary

Dosages

Carboplatin dosing by BSA is not recommended as it does not take into account of the
patient‘s renal function and/or desired platelet nadir.
The Calvert formula incorporates GFR to calculate the patient‘s carboplatin dose.
Although the creatinine clearance is always slightly higher than the GFR, the two estimates of
renal function are used interchangeably in the Calvert formula.
Calvert Formula [7]

Total Carboplatin dose = (target AUC)x(glomerular filtration rate (GFR) + 25)

Following the switch to the IDMS method of serum creatinine measurement, the National
Cancer Institute‘s Cancer Therapy Evaluation Program (NCI/CTEP) noted a potential for an
increase in carboplatin-related adverse events. This led to the publication of an action letter
on guidelines for carboplatin dosing in October 2010 [8]. In this action letter, the NCI/CTEP
made the following recommendations:

 They advised that the GFR used in the Calvert formula for carboplatin dosing should
not exceed 125 ml/min.
 They recommended capping the maximum carboplatin dose based on target area
under the curve (AUC).
88 M. Luque Cabal and P. Garcia Teijido

Maximum AUC-Based Carboplatin Dose

AUC Maximum carboplatin dose


6 900 mg
5 750 mg
4 600 mg
Back-conversion of IDMS creatinine to non-IDMS values was NOT permitted for carboplatin dosing.

The Cockcroft-Gault equation is the most common and an accurate formula used for
estimation of GFR in carboplatin dosing [9]. It was found to overestimate the creatinine
clearance in obese patients or in patients with abnormally low creatinine values [10]. In this
case, the most accurate and precise GFR estimates were obtained using the Wright formula
[11] for patients with a body mass index ≥30. This formula may be more accurate also in
elderly patients [9]. Overestimation of patients‘ renal function could result in higher than
intended carboplatin doses with a potential for increased toxicity.

Wright equation:
*Sex = 1 if female; 0 if male.

These concerns for patient safety led the Gynecologic Oncology Group (GOG) to make
further recommendations for carboplatin dosing [11]:

1. In patients with abnormally low serum creatinine they recommended using a


minimum serum creatinine value of 0.6 mg/dL when estimating GFR. This minimum
value was subsequently increased to 0.7 mg/dL to reflect the fact that the newer
IDMS values tend to be lower than non-IDMS.
2. Surgery and/or aggressive intravenous hydration can lead to artificially low serum
creatinine values, so for postoperative patients they indicate that clinicians could
consider using a more appropriate (higher) value from the preoperative period when
estimating GFR.
3. They recommend using an ― adjusted‖ rather than actual body weight in patients who
are overweight (those with BMI ≥ 25kg/m2). Actual weight is used for patients with
BMI < 25kg/m2
4. Patients who have ≥10% weight change from baseline or who experience CTCAE ≥
grade 2 renal toxicity (serum creatinine >1.5 ULN) require recalculation of the
carboplatin dose for subsequent cycles.
5. In patients who require carboplatin dose modification, if the creatinine at the time of
dose modification is lower than the baseline creatinine that was used, they
recommend using the prior (higher) creatinine value. If the creatinine at the time of
dose modification is higher than the baseline creatinine value, they recommended
using the current (higher) value. This is to ensure that patients receive the intended
dose reduction.
Carboplatin. Paraplatin®. CBDCA. 89

METHODS OF PREPARATION/ADMINISTRATION [4]


Aluminum reacts with Carboplatin causing precipitate formation and loss of potency,
therefore, needles or intravenous sets containing aluminum parts that may come in contact
with the drug must not be used for the preparation or administration of Carboplatin.
Carboplatin is mixed in 100mL to 250mL bag (5% Dextrose or Normal Saline) and
usually administered by an infusion lasting 15 minutes or longer. No pre- or post-treatment
hydration or forced diuresis is required.

SPECIAL INFORMATION AND CAUTIONS


Contraindications

 Severe hypersensitivity to carboplatin, other platinum compounds, mannitol.


 Severe myelosuppression, significant bleeding.
 Severe renal dysfunction.
 Pregnancy/lactation.

Elderly

Elderly patients may have more severe myelosuppression and neuropathy, so caution
should be exercised and dose reduction considered.

Pediatric

Safety and efficacy have not been established in this population. Clinically significant
hearing loss has been reported to occur in pediatric patients when carboplatin was
administered at higher than recommended doses in combination with other ototoxic agents.

Renal Impairment

Dose adjustment according to glomerular filtration rate is recommended, as explained


before. Treatment should be discontinued if creatinine clearance is lower than 20 ml/min.

Hepatic Impairment

Carboplatin does not require dose adjustment with hepatic impairment [4, 5].
90 M. Luque Cabal and P. Garcia Teijido

Immunizations

Live vaccines should not be applied while taking the treatment or for at least 6 months
afterwards. Other vaccines can be administered, though may not give as much protection as
usual. In any case, it is safe to be in contact with other people who have had live vaccines as
injections. There can be problems with oral vaccines. Any contacts with someone who has
had oral polio, cholera or typhoid vaccination recently, should be avoided.

Pregnancy

Carboplatin may cause fetal harm. Women of childbearing potential should be advised to
avoid becoming pregnant while on the treatment.

Breast-Feeding

It is not known if excreted in breast milk. Do not nurse while on the treatment.

WARNINGS
Emesis

Carboplatin has a moderate emetogenic risk, therefore guidelines recommend the


combination of a 5-HT3 receptor antagonist plus dexamethasone with or without aprepitant
[12].
Although no conclusive efficacy data exist, lengthening the duration of single intravenous
administration to 24 hours or dividing the total dose over five consecutive daily pulse doses
has resulted in reduced emesis.

Bone Marrow Suppression

This is dose-dependent and is also the dose-limiting toxicity. Peripheral blood counts
should be frequently monitored during carboplatin treatment and, when appropriate, until
recovery is achieved.
Median nadir occurs at day 21 in patients receiving single agent carboplatin.
Since anemia is cumulative, transfusions may be needed during treatment with
carboplatin, particularly in patients receiving prolonged therapy.
Marrow suppression is also increased in patients with impaired kidney function.
Carboplatin. Paraplatin®. CBDCA. 91

Nephrotoxicity

Limited nephrotoxic potential. Concomitant use with aminoglycosides has resulted in


increased renal and/or auditory toxicity.

Neurotoxicity

Peripheral neurotoxicity is infrequent. Its incidence is increased in patients older than 65


years and in patients previously treated with cisplatin.
Pre-existing cisplatin-induced neurotoxicity does not worsen in about 70% of the patients
receiving Carboplatin as secondary treatment.

Visual Disorders

Loss of vision (complete for light and colours) has been reported with doses higher than
those recommended in the package insert.
Vision appears to recover totally or to a significant extent within weeks of stopping these
high doses.

Ototoxicity

Hearing loss tended to be cumulative with increasing dose. Patients developing


ototoxicity tended to be older.

Allergic Reactions

These may occur within minutes of administration and should be managed immediately
with appropriate supportive therapy.
The risk of allergy (including anaphylaxis) is higher in patients previously exposed to
platinum.

Liver Toxicity

High dosages of Carboplatin (more than four times the recommended dose) have resulted
in severe abnormalities of liver function tests.
92 M. Luque Cabal and P. Garcia Teijido

TOXICITIES [4, 5]
System organ Very common Common Uncommon Rare
class (≥1/10) (≥1/100 to <1/10) (≥1/1000 to (≥1/10,000 and
<1/100) <1/1000)
Vascular disorders Hypotension
Infections and Infections
infestation
disorders
Nervous system Peripheral
disorders sensory
neuropathy
Hepatobiliary Hepatic toxicity, transient Elevation in Serious
disorders elevation in liver function serum bilirubin alterations in
tests, mainly SGOT and liver function
alkaline phosphatase. tests
Gastrointestinal Nausea and vomiting Diarrhea,
disorders Gastro-intestinal pain constipation
Respiratory, Bronchospasm
thoracic and
mediastinal
disorders
Renal and urinary Renal
disorders insufficiency

General disorders Asthenia, chills, Hypersensitivity,


and administration hypersensitivity anaphylaxis
site conditions reactions
Ear and eye Ototoxicity:
disorders high-frequency
hearing loss
above normal
speech and
occasional
tinnitus
Blood disorders Anemia,
thrombocytopenia,
leucopenia, BUN increase,
decrease creatinine
clearance, hyponatremia,
hypomagnesemia,
hypocalcemia,
hypokalemia
Very rare
Early hyponatremia Heart and vascular disorders
Secondary neoplasias Injection site reaction
Anorexia Hearing loss
Unknown frequency
Stomatitis Pain
Uremic-hemolytic syndrome Dehydration
Asthenia
Carboplatin. Paraplatin®. CBDCA. 93

DOSE MODIFICATIONS [4]


In general, the planned dose of chemotherapy should be delayed until neutrophil and
platelet counts have recovered to adequate levels such as:

Platelet count has recovered to ≥ 100 x 109/L


Neutrophil (ANC) count has recovered to ≥ 1.5 x 109/L

Toxicity Dose adjustment


Febrile neutropenia or Grade 4 neutropenia for >5-7 days 75%
or grade 4 thrombocytopenia
Grade 3 related organ/nonhematologic 75%
Grade 4 related organ/nonhematologic Discontinue

Interactions [5]

 Aminoglycosides: exacerbates nephrotoxicity and ototoxicity.


 Phenytoin: carboplatin decreases serum phenytoin levels.
 Warfarin: carboplatin increases risk of INR elevation and bleeding.
 Other nephrotoxic drugs: increase incidence of renal dysfunction.

CONCLUSION
Carboplatin has substituted cisplatin in the treatment of ovarian cancer, although it has
not meet its same results in other tumors. Its advantage is a more favorable toxic profile
except by its myelotoxicity. Carboplatin has a more comfortable way of administration and
the bone marrow toxicity can be predicted using dosing formulas adjusted to renal function.

REFERENCES
[1] Van der Vijgh WJF. Clinical pharmacokinetics of carboplatin. Clin. Pharmacokinet
1991;21(4):242-261.
[2] Lokich J. What Is the ‗‗Best‘‘ Platinum: Cisplatin, Carboplatin, or Oxaliplatin? Cancer
Investigation 2001; 19(7): 756–760.
[3] Hongo A, Seki S, Akiyama K, et al: A comparison of in vitro platinum-DNA adduct
formation between carboplatin and cisplatin. Int J Biochem 1994;26:1009-1116.
[4] FDA Profesional Drug Information Database. Carboplatin Injection 10mg/ml.
http://www.drugs.com/pro/carboplatin.html.
[5] Cancer Care Ontario-Carboplatin. October 2014. https://cancercare.on. ca/CCO_Drug
Formulary/pages/DfPdfContent.aspx?cat=DM&name=carboplatin.
[6] Go RS, Adjei AA. Review of the Comparative Pharmacology and Clinical Activity of
Cisplatin and Carboplatin. J Clin Oncol 1999; 17:409-422.
94 M. Luque Cabal and P. Garcia Teijido

[7] Calvert AH, Newell DR, Gumbrell LA, et al: Carboplatin dosage: Prospective
evaluation of a simple formula based on renal function. J Clin Oncol 1989; 7:1748-
1756.
[8] Craig AJ, Samol J, Heenan SD, Irwin AG and Britten A. Overestimation of carboplatin
doses is avoided by radionuclide GFR measurement. British Journal of Cancer 2012;
107: 1310–1316.
[9] Ainsworth NL, Marshall A, Hatcher H, Whitehead L, Whitfield GA, Earl HM.
Evaluation of glomerular filtration rate estimation by Cockcroft-Gault, Jelliffe, Wright
and Modification of Diet in Renal Disease (MDRD) formulae in oncology patients. Ann
Oncol 2012; 23(7):1845-53.
[10] Wright JG, Boddy AV, Highley M et al. Estimation of glomerular filtration rate in
cancer patients. Br J Cancer 2001; 84: 452–459.
[11] Collins IM, Roberts-Thomson R, Faulkner D, Rischin D, Friedlander M, Mileshkin L.
Carboplatin dosing in ovarian cancer: problems and pitfalls. Int J Gynecol Cancer.
2011 Oct;21(7):1213-8.
[12] Jordan K, Sippel C, Schmoll H-J. Guidelines for Antiemetic Treatment of
Chemotherapy-Induced Nausea and Vomiting: Past, Present, and Future
Recommendations. The Oncologist 2007;12:1143–1150.
In: The Easy Book of Cancer Pharmacology ISBN: 978-1-63485-038-4
Editor: Esther Una Cidon © 2016 Nova Science Publishers, Inc.

Chapter 11

CETUXIMAB. ERBITUX®

M. López-Gómez, B. García de Santiago, Y. Martín,


A. M. Jiménez-Gordo and E. Casado
Medical Oncology Department, University Hospital ―
Infanta Sofia,‖ Madrid, Spain

ABSTRACT
The epidermal growth factor receptor (EGFR, HER1, c-ErbB-1) is a transmembrane
glycoprotein that is a member of a subfamily of type I receptor tyrosine kinases including
EGFR, HER2, HER3, and HER4. The EGFR is constitutively expressed in many normal
epithelial tissues, including the skin and hair follicle, but overexpression of EGFR is also
detected in many human cancers including those of the head and neck, colon, and rectum.
In the case of head and neck squamous cell carcinoma, it is associated with poor
prognosis [1]. The activation of EGFR results in tumor growth as this union promotes
angiogenesis and metastases formation secondary to an increase in the motility and
adhesion of tumor cells [2].
Cetuximab is a monoclonal antibody directed against EGFR that inhibits its
downstream signalling pathways [3], and has a role in colorectal and head and neck
tumors. In colorectal cancer tumors with a mutations of codon 12 and 13 of exon 2 of the
KRAS gene are essentially insensitive to cetuximab treatment [4], and more recent
evidence show that mutations in NRAS are also predictive for a lack of benefit [5].
Therefore, prior to its administration in colorectal cancer, testing for RAS mutations
(KRAS and NRAS) must be performed. It must only be used in patients with KRAS and
NRAS exon wild-type metastatic colorectal cancer [6]. In the case of head and neck
tumors testing for KRAS is not necessary. In colon cancer it is approved in first line
setting in combination with FOLFIRI regimen, CPT-11 or as a single agent in patients
who have failed irinotecan and oxaliplatin based chemotherapy. In head and neck tumors
it can be used in monotherapy, in combination with radiotherapy or in combination with
platinum and 5 fluorouracil therapy.
Cetuximab has been associated with severe infusion reactions, including
anaphylaxis. Skin toxicity is a very common side effect. Furthermore, the presence and
severity of this skin rash has been shown to predict increased response and survival [7].


Miriam Lopez-Gomez, e-mail: miriam.lopez@movistar.es.
96 M. López-Gómez, B. García de Santiago, Y. Martín et al.

Keywords: cetuximab, antiEGFR, EGFR

INTRODUCTION
Cetuximab is an anti-EGFR monoclonal antibody that inhibits EGFR downstream
signalling pathways [3]. It is approved in metastatic colorectal cancer tumors with KRAS and
NRAS exon wild-type. Those patients with mutations of codon 12 and 13 of exon 2 of the
KRAS gene are essentially insensitive to this treatment [4], and more recent evidence show
that mutations in NRAS are also predictive for a lack of benefit [5]. In the case of head and
neck tumors testing for KRAS is not necessary.
Cetuximab has been associated with severe infusion reactions, including anaphylaxis.
Skin toxicity is avery common side effect. Furthermore, the presence and severity of this skin
rash has been shown to predict increased response and survival [7].

CLINICAL PHARMACOLOGY
Drug Classification [3]

Cetuximab is an epidermal growth factor receptor (EGFR) inhibitor.

Mechanism of Action [3]

Cetuximab binds specifically to the EGFR on both normal and tumor cells, and
competitively inhibits the binding of epidermal growth factor (EGF) and other ligands, such
as transforming growth factor-alpha. In vitro assays and in vivo animal studies have shown
that binding of cetuximab to the EGFR blocks phosphorylation and activation of receptor-
associated kinases, resulting in inhibition of cell growth, induction of apoptosis, and
decreased matrix metalloproteinase and vascular endothelial growth factor production. Signal
transduction through the EGFR results in activation of wild-type K-Ras protein.
However, in cells with activating K-Ras somatic mutations, the mutant K-Ras protein is
continuously active and appears independent of EGFR regulation.

Pharmacokinetics [3]

Intravenous (iv) infusions of cetuximab exhibited dose-dependent pharmacokinetics at


weekly dosis ranging from 5 to 500 mg/m2 body surface area.

Absorption Serum concentrations of cetuximab reach steady-state levels by the third weekly
infusion.
Distribution Mean volume of distribution after it was administered at an initial dose of 400 mg/m2
body surface area was approximately equivalent to the vascular space (2,9 L/m2,
range os 1,5 to 6,2 L/m2)
Cetuximab. Erbitux® 97

Metabolism Metabolism pathways involve the biodegradation of the antibody to smaller


molecules, i.e., small peptides or amino acids.
Elimination Mean half- life approximately 112 hours (range 63-230)

Mechanism of Resistance

Cetuximab is not indicated for treatment of RAS mutation positive colorectal cancer.

Indications [3]

1. Squamous cell carcinoma of the head and neck


 Cetuximab is indicated in combination with radiation therapy for the initial
treatment of locally or regionally advanced squamous cell carcinoma of the head
and neck.
 Cetuximab is indicated in combination with platinum-based therapy with 5 FU
for the first-line treatment of patients with recurrent locoregional disease or
metastatic squamous cell carcinoma of the head and neck.
 Cetuximab, as a single agent, is indicated for the treatment of patients with
recurrent or metastatic squamous cell carcinoma of the head and neck for whom
prior platinum-based therapy has failed.
2. RAS mutation negative colorectal cancer.
 Cetuximab is indicated for the treatment of RAS mutation negative (wild-type)
epidermal growth factor receptor (EGFR) expressing:
 in combination with FOLFIRI (irinotecan, 5-fluorouracil, leucovorin) or
FOLFOX (oxaliplatin, 5-fluorouracil, leucovorin) for first-line treatment.
 in combination with irinotecan in patients who are refractory to irinotecan-based
chemotherapy.
 as a single agent in patients who have failed oxaliplatin and irinotecan-based
chemotherapy or who are intolerant to irinotecan.

Dosages [3]

1. Squamous Cell Carcinoma of the Head and Neck

1.1. Erbitux in Combination with Radiation Therapy or in Combination with


Platinum-Based 48 Therapy with 5-FU
The recommended initial dose is 400 mg/m2 administered one week prior to initiation of
a course of radiation therapy or on the day of initiation of platinum based therapy with 5-FU
as a 120-minute intravenous infusion. Erbitux administration should be completed 1 hour
prior to platinum-based therapy with 5-FU. The recommended subsequent weekly dose (all
other infusions) is 250 mg/m2 infused over 60 minutes for the duration of radiation therapy
98 M. López-Gómez, B. García de Santiago, Y. Martín et al.

(6–7 weeks) or until disease progression or unacceptable toxicity when administered in


combination with platinum-based therapy with 5-FU.

1.2. Erbitux Monotherapy


The recommended initial dose is 400 mg/m2 administered as a 120-minute intravenous
infusion. The recommended subsequent weekly dose (all other infusions) is 250 mg/m2
infused over 60 minutes (maximum infusion rate 10 mg/min) until disease progression or
unacceptable toxicity.

2. Colorectal Cancer
The recommended initial dose, either as monotherapy or in combination with irinotecan
or FOLFIRI (irinotecan, 5-fluorouracil, leucovorin), is 400 mg/m2 administered as a 120-
minute intravenous infusion (maximum infusion rate 10 mg/min). Complete Erbitux
administration 1 hour prior to FOLFIRI.
The recommended subsequent weekly dose, either as monotherapy or incombination with
irinotecan or FOLFIRI, is 250 mg/m2 infused over 60 minutes 76 (maximum infusion rate 10
mg/min) until disease progression or unacceptable 77 toxicity. Complete Erbitux
administration 1 hour prior to FOLFIRI.

Methods of Preparation/Administration [3]

Cetuximab should never be administered as an intravenous push or bolus. Administer via


infusion pump or syringe pump. Administer through a low protein binding 0.22-micrometer
in-line filter.
As with other parenteral drug products, Cetuximab should be inspected visually for
particulate matter and discoloration prior to administration.
The solution should be clear and colorless and may contain a small amount of easily
visible, white, amorphous, cetuximab particulates.
The maximum infusion rate should be 10 mg/min.

Special Cautions [3]

Contraindications
It is contraindicated in patients with serious hypersensitivity reactions (grade 3 and 4). Its
combination with chemotherapy is contraindicated in patients with metastatic colorectal
cancer with RAS mutated or unknown.

Elderly
No overall differences in safety or efficacy has been observed in this population
compared to younger patients.

Pediatric
The safety and efficacy of cetuximab in this population has not been established.
Cetuximab. Erbitux® 99

Renal Impairment
It has not been studied in patients with renal impairment.

Hepatic Impairment
It has not been studied in patients with hepatic impairment.
Immunisations
Live vaccines should not be applied while taking the treatment or for at least 6 months
afterwards. Other vaccines can be administered, though may not give as much protection as
usual.
In any case, it is safe to be in contact with other people who have had live vaccines as
injections. There can be problems with oral vaccines. Any contacts with someone who has
had oral polio, cholera or typhoid vaccination recently, should be avoided.

Warnings [3]

Infusion Reactions
To prevent serious infusion reactions all patients should be premedicated prior to
Cetuximab. Premedications should include an H1 antagonist (e.g., 50 mg of
diphenhydramine) intravenously 30-60 minutes prior to the first dose; premedication should
be administered for subsequent Erbitux doses based upon clinical judgment and presence/
severity of prior infusion reactions.
Cetuximab serious infusion reactions occur in 2-5% of patients. Approximately 90%
occurs with the first infusion. These reactions include symptoms of airway obstruction
(bronchospasm, stridor, and hoarseness), hypotension, shock, loss of consciousness,
myocardial infarction and/or cardiac arrest.
Patients should be monitored for 1 hour following Cetuximab infusions in a setting with
resuscitation equipment and other agents necessary to treat anaphylaxis (e.g., epinephrine,
corticosteroids, intravenous antihistamines, bronchodilators and oxygen).
Some patients should be monitored longer to confirm resolution of the event. Cetuximab
should be immediately and permanently discontinued in patients with serious infusion
reactions.

Hypomagnesemia and Electrolyte Abnormalities


The incidence of cetuximab-related hypomagnesemia is higher with the combinations
with cisplatin than with carboplatin. The onset of hypomagnesemia and accompanying
abnormalities occur days to months after the initiation of the drug. Patients should be
monitored for hypomagnesemia, hypocalcemia and hypokalemia during and at least 8 weeks
following the completion of cetuximab, and electrolytes depletion should be corrected.

Dermatology Toxicity
Treatment of skin rash might include topical clyndamicin 2% plus hydrocortisonse 1% in
mild pustular or papular eruption.
In the case of moderate pustular, papular eruption or erythema doxyciline 100 mgr o.d.
should be added for minimum 4 weeks and continuing for the duration of treatment.
100 M. López-Gómez, B. García de Santiago, Y. Martín et al.

In severe, extensive, painful and intolerate rash treatment with cetuximab should be
discontinued.

Cardiopulmonary Arrest
Closely monitor serum electrolytes during and after Erbitux.
Pulmonary Toxicity
Interrupt therapy for acute onset or worsening of pulmonary symptoms.

Toxicity [3]

System Organ Class Very Common Common ≥1/1000 Uncommon Rare


≥1/10 to <1/10 ≥1/1,000 to (≥ 1/10.000
<1/1000 a <1/1.000)
Blood and lymphatic Hypogmagnesemia Hypocalcemia
disoders
Cardiovascular Deep venous
disorders thrombosis,
pulmonar
embolism
Respiratory disorders Intersticial lung
disease
Eye disorders Conjuntivitis Blepharitis,
keratitis
Nervous System Cephalea
disorders
Gastrointestinal Mucositis, Increase Diarrhea, nausea,
disorders of levels of vomiting,
transaminases anorexia,
(ASAT, ALAT) and mucositis
alkaline
phosphatase.
Immunological Infusion-related Severe infusion-
disorders reactions related reactions
Skin and nail Rash, changes in
disorders subcutaneous
cellular tissue.
General disorders Dehydratation
secondary to
diarrhea
Musculoskeletal
disorders
Very rare (<1/10.000)
Stevens Johnson syndrome
Frequency unknown
Aseptic meningitis, skin lesions sobreinfection.
Cetuximab. Erbitux® 101

Dose Modifications [3]

1. Infusion Reactions
The infusion rate should be reduced by 50% for NCI CTC grade 1 and 2 and non-serious
NCI CTC grade 3 infusion reactions. Cetuximab should be permanently discontinued for
serious infusion reactions requiring medical intervention and/or hospitalization.

2. Dermatological Toxicity

Severe Cetuximab Outcome Cetuximab dose


acneiform rash modification
1st ocurrence Delay infusion to 1-2 Improvement Continue at 250 mgr/m2
weeks Not improvement Discontinue cetuximab
2nd ocurrence Delay infusion to 1-2 Improvement Continue at 200 mgr/m2
weeks Not improvement Discontinue cetuximab
3rd occurrence Delay infusion to 1-2 Improvement Continue at 150 mgr/m2
weeks Not improvement Discontinue cetuximab
4th ocurrence Discontinue Cetuximab

Interactions [3]

There are no known significant interactions.

CONCLUSION
Cetuximab is a monoclonal antibody directed against EGFR receptor resulting in an
inhibition of tumor growth and metastases. It is usually well tolerated and its side effects very
manageable, being acneiform rash, diarrhea and hypomagnesemia the most frequently
detected. Serious infusion reactions occur in approximately 3% of patients, and in this setting
cetuximab must be inmediatly interrumpted and permanently discontinued.
Currently it is approved for the treatment of metastastic colorectal cancer and squamous
cell carcinoma of the head and neck. Prior to its administration in metastatic colorectal cancer
determination of status of RAS mutations (K-RAS and N-RAS) must always be performed, as
the administration of Cetuximab in RAS mutated colorectal cancer may result in lower
survival of these patients.
In head and neck squamous cell carcinoma RAS is not predictive of response to
cetuximab, therefore it can be administered without determination of mutation status of RAS.
The presence and severity of skin rash toxicity has been shown to predict increased response
and survival in patients treated with cetuximab, and can be used as a predictive marker of this
therapy [1-3].
102 M. López-Gómez, B. García de Santiago, Y. Martín et al.

REFERENCES
[1] Dassonville O, Formento JL, Francoual M, Ramaioli A, Santini J, Schneider M et al.
Expression of epidermal growth factor receptor and survival in upper aerodigestive tract
cancer. J Clin Oncol. 1993;11(10):1873.
[2] Woodburn JR. The epidermal growth factor receptor and its inhibition in cancer
therapy. Pharmacol Ther. 1999;82(2-3):241.
[3] Package insert. Cetuximab (Erbitux®). Branchburg NJ. Imclone Systems Incorporated
2013.
[4] De Roock W, Piessevaux H, De Schutter J, Janssens M, De Hertogh G, Personeni N et
al. KRAS wild type state predicts survival and is associated to early radiological
response in metastatic colorectal cancer treated with cetuximab. Ann Oncol 2008; 19:
508-5015.
[5] Sorich MJ, Wiese MD, Rowland A, Kichenadasse G, McKinnon RA and Karapetis CS.
Extended RAS mutations and anti-EGFR monoclonal antibody survival benefit in
metastatic colorectal cancer: a meta-analysis of randomized controlled trials. Ann Oncol
2015; 26(1):13-21.
[6] Vale CL, Tierney JF, Fisher D, Adams RA, Kaplan R, Maughan TS et al. Does anti-
EGFR therapy improve outcome in advanced colorectal cancer? A systematic review
and meta-analysis. Cancer Treatment Reviews 2012; 38: 618-625.
[7] Berlin J, Van Cutsem E, Peeters M et al. Predictive value of skin toxicity severity for
response to panitumumab in patients with metastatic colorectal cancer (mCRC): a
pooled analysis of five clinical trials (abstract). J Clin Oncol. 2007;25 (June 20, suppl.)
4134.
In: The Easy Book of Cancer Pharmacology ISBN: 978-1-63485-038-4
Editor: Esther Una Cidon © 2016 Nova Science Publishers, Inc.

Chapter 12

CISPLATIN, PLATINOL®, PLATINOL®-AQ

M. Luque Cabal1, and P. Garcia Teijido2


1
Medical Oncology Department, University Hospital of Asturias,
Oviedo, Spain
2
Medical Oncology Department, ―San Ag ustin‖ Hospital,
Aviles, Spain

ABSTRACT
Cisplatin, CDDP, DDP or cis-diamminedichloroplatinum (II) is a heavy metal
platinum complex similar to the bifunctional alkylating agents. Intracellularly, water
displaces the chloride to form highly reactive charged platinum complexes. These
complexes covalently bind to DNA, leading to intrastrand, interstrand, and protein cross-
linking of DNA. Formation of these DNA-adducts results in inhibition of DNA synthesis
and function as well as inhibition or transcription, leading to apoptosis. It is an effective
and widely used chemotherapeutic agent for the treatment of solid tumors including
ovarian, testicular, cervical, lung, head and neck and bladder cancers in adult patients. It
is used also for many types of cancer in children, including neuroblastoma, osteosarcoma
and hepatoblastoma. Dose-limiting side effects of cisplatin include nephrotoxicity,
neurotoxicity and ototoxicity.

Keywords: cisplatin, CDDP, cis-diamminedichloroplatinum (II)

INTRODUCTION
Cisplatin is an inorganic complex formed by an atom of platinum surrounded by chlorine
and ammonia atoms in the cis position of a horizontal plane. The compound cis-PtCl2(NH3)2
was first described by M. Peyrone in 1845 (known as Peyrone‘s salt). In the 1960s, Barnett
Rosenberg and van Camp et al. at Michigan State University in the USA observed that a
current delivered between platinum electrodes inhibited binary fission in Escherichia coli.


malucabal@yahoo.es.
104 M. Luque Cabal and P. Garcia Teijido

The bacteria grew to 300 times their normal length, but cell division fails. These inhibitory
effects were later found to be related to the formation of inorganic platinum-containing
moieties in the presence of ammonium and chloride ions. Rosenberg then conducted a series
of experiments to test the effects of various platinum coordination complexes on sarcomas
artificially implanted in rats. This study found that cis-diamminedichloroplatinum (cisplatin)
was the most effective of this group, which was introduced in the clinical practice in the early
1970´s, and was approved by the United States Food and Drug Administration (FDA) in 1978
[1].

CLINICAL PHARMACOLOGY
Drug Classification

Platinum analog.

Mechanism of Action

Cisplatin is a platinum(II) complex with two ammonia groups in the cis position and two
chloride ‗‗leaving‘‘ groups. This molecule has to be activated through a series of spontaneous
aquation-reactions in which the chloride groups are replaced by water molecules. This
reaction is driven by the high concentration of water and low concentration of chloride in the
tissues. The monoaquated form is a highly reactive species. It interacts with nucleophilic N7-
sites of purine bases in DNA to form DNA–protein and DNA–DNA interstrand (>90%) and
intrastrand (<5%) crosslinks. The last ones are the lesions largely responsible for the
cytotoxic action. This DNA damage is recognized by over 20 proteins, which transduce DNA
damage signals to downstream effectors. So, several signal transduction pathways are
activated, including those involving ATR, p53, p73, and MAPK, and culminate in the
activation of apoptosis. These aquated metabolites are also prone to interact with a wide
number of cytoplasmic substrates, and in particular with endogenous nucleophiles such as
reduced glutathione (GSH), methionine, metallothioneins and proteins (via their cysteines).
Thus, cytoplasmic cisplatin has the potential to deplete reduced equivalents and to tilt the
redox balance toward oxidative stress [2].

PHARMACOKINETICS [3]
Absorption Not applicable as intravenous (iv) administration
Distribution Following iv administration, cisplatin is widely distributed with highest levels
in kidney, liver, intestines and prostate. It binds rapidly and extensively to
plasma proteins. Less than 10% remaining as cisplatin unbound in the plasma
1 hour after infusion. The median volume of distribution is 41 L/m2 (range
20 L/m2 to 80 L/m2). It accumulates in body tissues and has been detected until
6 months after the last dose of the drug. It does not cross blood-brain-barrier. It
crosses placenta and appears in breast milk.
Cisplatin, Platinol®, Platinol®-AQ 105

Absorption Not applicable as intravenous (iv) administration


Metabolism Chloride ligands of the cisplatin molecule are displaced by water thus forming
positively charged platinum complexes that react with nucleophilic sites.
Clearance of platinum compounds is triphasic in nature, with a distribution
half-life (t1/2 alpha) of 13 min, elimination half-life (t1/2 beta) of 43 min, and
terminal half-life (t1/2 gamma) of 5.4 days for total cisplatin [4].
Excretion More than 90% is eliminated in urine. Between 10-40% of a given dose of
cisplatin is excreted in the urine in 24 h, with 35-50% being excreted in the
urine after 5 days of administration. 15% of the drug is excreted unchanged.

MECHANISMS OF RESISTANCE [5, 6]


a. Pre-target resistance:
 Impaired blood flow: circumstances that cause a decrease in blood pressure or an
increase in tumor tissue pressure may produce a lower drug delivery.
 Increase in extracellular pH.
 Decreased drug uptake: changes in cell membrane fluidity that increases its
rigidity, down-regulation of the copper transporter CTR1 and microtubule
alterations with defective formation of the endocytic recycling compartment may
decrease cytoplasmic cisplatin levels.
 Increased drug efflux: up-regulation of the copper-transporting P-type adenosine
triphosphatases ATP7A/ATP7B and other pumps like MRP2
(multidrugresistance-associated-protein-2), cMOAT (canalicular Multispecific
Organic Anion Transporter)/glutathione-Xconjugate pump, MRP1, p-
glycoprotein and major vault/lung resistance-related protein (MVP/LRP);a
higher intracellular pH also may increase cisplatin efflux.
b. On-target resistance:
 Drug detoxification: some studies suggest that increased gluthation (GSH) and
other GSH-related enzymes may cause resistance by binding or inactivating
cisplatin.
 DNA repair: increased proficiency of cellular mechanisms that detect (miss-
matched repair (MMR) system) and remove cisplatin DNA-lesions (nucleotide
excision repair (NER) system), of some polymerases that allow DNA synthesis
beyond DNA adducts (POLH and REV3) and of homologous recombination,
cause cisplatin resistance.
c. Post-target resistance:
 Reduced apoptotic response: defects in the signal transduction pathways that
normally elicit apoptosis in response to DNA damage as well as problems with
the cell death executioner machinery itself.

INDICATIONS [7, 8]
 Germ cell tumors.
 Gynecological cancers: ovarian cancer, endometrial cancer, cervical cancer.
106 M. Luque Cabal and P. Garcia Teijido

 Advanced or metastatic bladder carcinoma.


 Squamous cell carcinoma of the head and neck.
 Non-small cell lung cancer.
 Small cell lung cancer.
 Other uses: adrenocortical cancer, neuroendocrine tumors, breast cancer, lymphoma,
thymoma, unknown primary tumors, skin cancer.

Dosages

Dosage of cisplatin is related to the kind of tumor and the polychemotherapy scheme
used. Dosage ranges between 20-100 mg/m2 once every 3-4 weeks or 15-20 mg/m2 daily for
five days. Doses greater than 100 mg/m2/cycle once every 3 to 4 weeks are rarely used.
Most frequent schedules (alone or in combination with other drugs) are as follows:

 50-100 mg/m2 day 1 every 3-4 weeks


 20-25 mg/m2 days 1-3 every 3-4-weeks
 20 mg/m2 days 1-5 every 3-4 weeks

METHODS OF PREPARATION/ADMINISTRATION [2]


Cisplatin is available in the form of sterile, unpreserved, single-dose vials [10 mg/10 mL,
50 mg/50 mL and 100 mg/100 mL] at a concentration of 1 mg/mL. Unopened vials should be
stored at room temperature.
Cisplatin solutions must not be refrigerated or frozen as a precipitate will form. The
solutions should be protected from light. Iv needles, syringes or sets that have aluminum
components must not be used in the preparation or administration of cisplatin. An interaction
between aluminum and platinum will occur resulting in the formation of a black precipitate,
accompanied by a loss of potency.
Hydration is required to minimize nephrotoxicity. The manufacturer recommends pre-
treatment hydration with 1 or 2 L of fluid infused 8-12 hours prior to a cisplatin dose,
hydration with normal saline, hypertonic saline infusion, and administration of mannitol, or
furosemide-induced diuresis is used to effectively decrease cisplatin-induced nephrotoxicity.
Urine output should be maintained at > 90 mL/m²/hour during administration. Lower doses of
cisplatin are given with less intensive hydration.
A practical way of hydration is as follows:

 Pretreatment hydration

Hydration may be achieved by iv infusion of 2 litres of either sodium chloride 0.9% or


glucose-saline over a 2 hour period.
During the last 30 minutes of the pretreatment hydration or after the hydration, 375 mL of
10% mannitol injection may be administered via a side-arm drip.
Cisplatin, Platinol®, Platinol®-AQ 107

 Preparation of cisplatin infusion


Cisplatin injection should be added to 1 litre of sodium chloride iv infusion 0.9%.

 Treatment

Following prehydration, the cisplatin infusion should be administered over 1-2 hours. It
has been proposed that longer infusions (6-8 hours) may decrease gastrointestinal and renal
toxicities. The iv flask should be covered to preclude light.

 Post-treatment hydration

Adequate hydration and urinary output must be maintained during the 24 hours following
infusion. It has been proposed that iv hydration should continue after treatment with the aim
to administer 2 litres of sodium chloride iv infusion 0.9% or glucosesaline over 6-12 hours.
CDDP is not active orally and must not be administered intramuscular or intrathecal.

SPECIAL INFORMATION AND CAUTIONS [2]


As cisplatin is highly emetogenic, it is recommended to use an effective antiemetic
treatment schedule, containing a 5-HT3 antagonist plus a corticosteroid and a NK1 antagonist
[9].

Contraindications

Use of CDDP is contraindicated in patients with a history of hypersensitivity to cisplatin


or other platinum analogs. It is also contraindicated in pregnancy. Although it is not known
whether cisplatin is excreted in breast milk, to avoid possible harmful effects in the infant,
breastfeeding is not advised during cisplatin therapy.

Elderly Patients

Though data are limited, cisplatin seems to be well tolerated by patients 70 years and
older and dose intensity does not seem to influence renal function deterioration. However,
caution should be taken into consideration in the elderly population [10].
In four clinical trials of combination chemotherapy, 1484 patients received cisplatin
either in combination with cyclophosphamide or paclitaxel. In all four trials, elderly patients
experienced more severe neutropenia, thrombocytopenia and leukopenia than younger
patients. In the two trials where non-hematologic toxicity was evaluated according to age,
elderly patients had a numerically higher incidence of peripheral neuropathy than younger
patients. Other reported clinical experience suggests that elderly patients may be more
susceptible to myelosuppression, infectious complications, and nephrotoxicity than younger
patients [11].
108 M. Luque Cabal and P. Garcia Teijido

Cisplatin is known to be substantially excreted by the kidney and is contraindicated in


patients with pre-existing renal impairment. Because elderly patients are more likely to have
decreased renal function, care should be taken in dose selection, and renal function should be
monitored.
Geriatric patients may also be at increased risk with hydration regimens. These regimens
should take into account the following conditions for the patient: adequate renal function,
clinically euvolemic prior to administration of cisplatin, no contraindication to saline loading
(e.g., uncompensated cardiac conditions, anasarca), and ability to comply with recommended
oral hydration protocol, or expectation that volume status can be maintained [3].

Pediatric Patients

Studies have shown that cisplatin causes irreversible ototoxicity in children with a
prevalence rate of 10% to 85%. Apparently the total cumulative dosage of cisplatin and the
age at what CDDP is administered are related to the sensorineural hearing loss. However,
more research is needed to determine the exact total dosage amount that separates minimal
hearing losses from severe hearing impairments. Moreover it is not clear the role of the age in
cisplatin-derived ototoxicity. Some studies suggest that older age is a protective factor and
others found less hearing loss if younger than three years of age [12, 13].
All children should have audiometric monitoring prior to therapy and to each subsequent
dose, and for several years post treatment. Advanced testing methods may allow for earlier
detection of hearing loss in an attempt to facilitate the rapid initiation of interventions that can
limit the potential adverse impact of hearing impairment on a child‘s cognitive and social
development.

Renal Impairment [14, 15]

Cisplatin induces nephrotoxicity, which is cumulative. Dose adjustment is necessary.

Creatinine clearance (CrCl) [14]


>60 ml/min 75%
45 ml/min 50%
30 ml/min Contraindicated. Switch to carboplatin

Creatinine clearance (CrCl) [15]


>50 ml/min 100%
10-50 ml/min 75%
<10 ml/min 50%

Creatinine clearance (CrCl) British Columbia (BC) Cancer Agency


>60 ml/min 100%
45-59 ml/min 75%
<45 ml/min Contraindicated. Switch to carboplatin
Cisplatin, Platinol®, Platinol®-AQ 109

Haemodialysis – Give 50% dose. However, there is no evidence for this practice. BC
Cancer Agency advises dialysis within 3 hours of giving dose.

Hepatic Impairment

Cisplatin is primarily excreted by the kidney and therefore is unlikely to require dose
adjustments in patients with hepatic dysfunction. There are no formal studies evaluating the
dosing of these agents in patients with liver failure [3].

Immunizations

Live vaccines should not be applied while taking the treatment or for at least 6 months
afterwards. Other vaccines can be administered, though may not give as much protection as
usual. In any case, it is safe to be in contact with other people who have had live vaccines as
injections. There can be problems with oral vaccines. Any contacts with someone who has
had oral polio, cholera or typhoid vaccination recently, should be avoided [3].

TOXICITIES [2, 16]


System organ Very common Common Uncommon Rare (≥1/10,000
class (≥1/10) (≥1/100 to <1/10) (≥1/1000 to <1/100) and <1/1000)
Vascular Myocardial
disorders infarction
Infections and Infections, sepsis
infestation
disorders
Nervous system Peripheral
disorders sensory
neuropathy.
Paresthesias and
numbness in a
stocking-glove
pattern.
Loss of motor
function, focal
encephalopathy
and seizures.
Cardiac Heart disorders (ST-
disorders T abnormalities,
bundle branch
block, atrial
fibrillation, angina,
supraventricular
tachycardia)
Gastrointestinal Early and delayed Stomatitis
disorders nausea and vomiting
(<70 mg/m2: moderate
emetogenic potential;
>70 mg/m2:high
emetogenic potential)
110 M. Luque Cabal and P. Garcia Teijido

Table. (Continued)

System Very common Common Uncommon Rare (≥1/10,000


organ class (≥1/10) (≥1/100 to <1/10) (≥1/1000 to <1/100) and <1/1000)
Respiratory, dyspnea, pneumonia,
thoracic and respiratory
mediastinal insufficiency
disorders
Renal and Cumulative renal
urinary disorders toxicity;
nephrotoxicity is
dose-dependent and
dose-limiting and
manifested by renal
tubular damage.
General disorders Metallic taste of food Hypersensitivity,
and and water, anaphylaxis
administration Injection site reaction
site conditions
investigations Anemia, Hypomagnesemia Hipoalbuminemia
thrombocytopenia,
leucopenia
hyponatremia
Secondary Secondary
neoplasias neoplasias (acute
leukemia)
Hearing disorders Ototoxicity: high-
frequency hearing
loss above normal
speech and
occasional tinnitus.
Fertility disorders Azoospermia,
impotence and
sterility
Very rare
Cardiac arrest
Others whose frequency is unknown
Coombs-positive hemolytic anemia
Raynaud´s syndrome
Neurologic disorders: Ischemic and hemorrhagic strokes, Lhermitte´s sign, myelopathy, cerebral arteritis.
Thrombotic microangiopathy
Venous thromboembolism
Aortic thrombosis
Rash, alopecia
SIADH
Hepatic toxicity: transient elevation in liver function tests, mainly AST and serum bilirubin.
Dehydration
Hyperuricemia
Hyperamilasemia
Electrolyte abnormalities, mainly, hypocalcemia and hypokalemia.
Ocular disorders: optic neuritis, papilledema, cerebral blindness, altered color perception
Muscle cramps
Cisplatin, Platinol®, Platinol®-AQ 111

DOSE MODIFICATIONS
If Toxicities Related to Grades: [2, 16]

Toxicity Dose modification


Grade 4 thrombocytopenia, Grade 4 neutropenia during ≥5 days,
thrombocytopenic bleeding, febrile neutropenia 25%*
Grade 2 neurotoxicity/ototoxicity
Other grade 3 non-hematologic toxicity
Renal insufficiency creatinine clearance
46-60 ml/min 75%
30-45 ml/min 50%
<30 ml/min Discontinue
Grade 3 or 4 neurotoxicity/ototoxicity Discontinue
Other grade 4 non-hematologic/organ
toxicity
Hemolysis, optic neuritis, arterial thromboembolism, severe
hypersensitivity reactions, grade 3 or 4 ↑ liver function tests
* Do not retreat until platelets ≥100 x 109/L, ANC ≥ 1.5 x 109/L, toxicity has recovered to ≤ grade 2 (grade 1
for neurotoxicity) and creatinine ≤ UNL.

INTERACTIONS [3]
 Loop diuretics (furosemide) and aminoglycosides increase ototoxicity when used
with cisplatin.
 Aminoglycosides and amphotericin B can increase renal toxicity.
 Cisplatin decreases the effect of phenytoin.
 Cisplatin decreases the renal clearance of etoposide, methotrexate, ifosfamide and
bleomycin, increasing their accumulation.
 Cisplatin is inactivated by amifostine and mesna.
 Cisplatin delays paclitaxel excretion, so cisplatin should be administered after
paclitaxel when they are administered together.
 Radiation therapy as cisplatin acts as radiosensitizing agent.

CONCLUSION
Cisplatin is one of the most active drugs in the treatment of solid tumors. It has a narrow
therapeutic index, so it is important to know its management. Although other platinum
derivatives have been introduced in the clinical practice, cisplatin continue to be the
cornerstone of treatment of a wide range of carcinomas.
112 M. Luque Cabal and P. Garcia Teijido

REFERENCES
[1] Rosenberg B, Van Camp L, Krigas T: Inhibition of cell division in Escherichia coli by
electrolysis products from a platinum electrode. Nature 1965; 205(4972): 698-699.
[2] Siddik ZH. Cisplatin: mode of cytotoxic action and molecular basis of resistance.
Oncogene 2003; 22:7265–7279.
[3] Cisplatin- FDA prescribing information, side effects and uses (Accessed 25/05/2015).
http://www.drugs.com/pro/cisplatin.html.
[4] Timerbaev AR, Hartinger CG, Aleksenko SS, Keppler BK. Interactions of antitumor
metallodrugs with serum proteins: advances in characterization using modern analytical
methodology. Chem Rev 2006; 106: 2224–2248.
[5] L Galluzzi, L Senovilla, I Vitale, J Michels, I Martins, O Kepp, M Castedo and G
Kroemer. Molecular mechanisms of cisplatin resistance. Oncogene (2012) 31, 1869–
1883.
[6] Stewart D.J. Mechanisms of resistance to cisplatin and carboplatin. Critical Reviews in
Oncology/Hematology 2007;63: 12–31.
[7] W Matysiak, K Gustaw-Rothenberg. Pharmacological profile and clinical features of
cisplatin. Journal of Pre-Clinical and Clinical Research 2009; 3(1):20-23.
[8] Go RS, Adjei A.A. Review of the Comparative Pharmacology and Clinical Activity of
Cisplatin and Carboplatin. J Clin Oncol 17:409-422.
[9] Jordan K, Sippel C, Schmoll H-J. Guidelines for Antiemetic Treatment of
Chemotherapy-Induced Nausea and Vomiting: Past, Present, and Future
Recommendations. The Oncologist 2007;12:1143–1150.
[10] Polovich M, White JM, Kelleher LO, eds. 2005. Chemotherapy and biotherapy
guidelines and recommendations for practice. 2nd ed. Pittsburgh, PA: Oncology
Nursing Society.
[11] Cubillo A, Cornide M, López JL, Molina R, Feliu J, Espinosa E, Zamora P, de Castro J,
Ordoñez A, González Barón M. Renal tolerance to cisplatin in patients 70 years and
older. Am J Clin Oncol. 2001 Apr; 24(2):192-197.
[12] Bertolini, P., Lassalle, M., Mercier, G., Raquin, M., Izzi, G., Carradini, N., et al. (2004).
Platinum compound-related ototoxicity in children: Long-term follow-up reveals
continuous worsening of hearing loss. Journal of Pediatric Hematology and Oncology,
26(10), 649-655.
[13] Kushner, B., Budnick, A., Kramer, K., Modak, S. and Cheung, N. (2006). Ototoxicity
from high-dose use of platinum compounds in patients with neuroblastoma. Cancer,
107(2), 417-422. Protective.
[14] Kintzel PE, Dorr RT. Anticancer drug renal toxicity and elimination: dosing guidelines
for altered renal function. Cancer Treat Rev 1995;21:33-64.
[15] Bennett WM et al. Dosing Guidelines for Adults. 4th ed. American College of
Physicians, 1999.
[16] Cancer Care Ontario-Cisplatin (February 2015). https://cancercare.on.ca/
CCO_DrugFormulary/pages/DfPdfContent.aspx?cat=DM&name=cisplatin.
In: The Easy Book of Cancer Pharmacology ISBN: 978-1-63485-038-4
Editor: Esther Una Cidon © 2016 Nova Science Publishers, Inc.

Chapter 13

CRIZOTINIB. XALKORI®

V. Wood
Clinical Oncology, University Hospital Southampton,
Southampton, UK

ABSTRACT
Crizotinib is an oral small molecule multiple tyrosine kinase inhibitor (TKI). It is
indicated for use in the treatment of advanced non-small cell lung cancers (NSCLC) that
express an anaplastic lymphoma kinase (ALK) gene rearrangement. In cells that have the
ALK fusion oncogene, crizotinib has been demonstrated to inhibit growth and induce
apoptosis. It is metabolized predominantly by CYP3A and therefore co-administration of
strong inhibitors and inducers of CYP3A should be avoided.
The recommended dosage should be 250 mg twice a day continuously until no
longer clinically beneficial.
Crizotinib is generally well tolerated with most adverse events being grade 1 or 2.
Common side effects include visual disturbance, diarrhoea, vomiting, oedema and
fatigue. Rare but potentially more serious side effects include pneumonitis, QT
prolongation, bradycardia and hepatic dysfunction.

Keywords: crizotinib, non-small cell lung cancer

INTRODUCTION
Crizotinib is a multiple tyrosine kinase inhibitor that targets anaplastic lymphoma kinase
(ALK), hepatocycte growth factor receptor (HGFR, c-met) and ROS-1 tyrosine kinases [1].
ALK was first described in anaplastic large cell lymphoma. It has since been found in
multiple malignancies including non–small cell lung cancer, inflammatory myofibroblastic
tumours and more rarely in breast, colon and renal cell cancers. It was first recognized as a
potential target in non-small cell lung cancer in 2007 [2].


victoriawood@live.co.uk.
114 V. Wood

Approximately 5% of non-small cell lung cancers have an EML4-ALK gene fusion


rearrangement [3]. Those who are most likely to have the rearrangement have
adenocarcinoma histology, are non-smokers and are below the age of 50 years old [2]. In the
EML4-ALK rearrangement the ALK gene located on Chromosome 2p23 is fused with the
echinoderm microtubule-associated protein-like 4 (EML4) gene to form an EML4-ALK
fusion protein [3]. This fusion results in a kinase that is constitutively active, causing up
regulation in cell signalling and gene expression resulting in an increase in cell proliferation
and survival in cells expressing this gene. Therefore by selective inhibition of this pathway
with crizotinib, malignant cells will be preferentially killed but normal cells should be
relatively inoculated.
Crizotinib has demonstrated superiority in phase 3 trials compared to standard
chemotherapy in both the first line and second line setting, in terms of response rates and
progression free survival. PROFILE 2014 demonstrated a significantly improved progression-
free survival with crizotinib with 10.9 months versus 7.0 months compared with standard
chemotherapy in the first line setting, with a response rate of 75% compared with 45% [9].
The median duration of response was 11.3 months versus 5.3 months [9]. The PROFILE 1007
trial demonstrated benefit of crizotinib in the second line setting compared to standard
chemotherapy with an improved response rate of 65% versus 20% and significantly improved
progression free survival of 7.7 months versus 3.3 months [8]. There was no significant
difference in overall survival benefit for crizotinib in either trial. It has been suggested that
this reflects subsequent treatment, as there was a high percentage of chemotherapy patient‘s
crossing over to crizotinib after progressing on chemotherapy in both trials.

DRUG CLASSIFICATION
Crizotinib is a TKI.

MECHANISM OF ACTION
Crizotinib is a selective small molecule TKI that targets ALK, C-MET and ROS-1
tyrosine kinases. It competitively binds within the ATP-binding pocket of the target kinases
resulting in the inhibition of phosphylation and subsequent signal transduction [4]. The
inhibition results in G1-S phase cell cycle arrest [2]. The efficacy of crizotinib is dose
dependent [2].
Crizotinib. Xalkori® 115

PHARMACOKINETICS [1, 4, 5]
Absorption Solubility is pH dependent
Median time to peak concentration is 4 hours
Bioavailability 43% (range of 32-66%)
High fat meal reduces bioavailability by ~14%
Distribution Excessive distribution to tissues (volume of distribution following IV
administration = 1772L)
Crosses blood brain barrier (although poor central nervous system (CNS)
activity)
91% plasma protein binding
Metabolism Hepatic metabolism
Oxidation of piperidine ring to crizotinib lactam (active metabolite) and O-
desalkylation with subsequent Phase 2 conjugation of O-dealkyated
metabolites to inactive metabolites (O-desalky crizotinib and O-desalkyl
crizotinib lactam)
Excretion Faeces = 63% (53% unchanged drug)
Urine = 22% (2% unchanged drug)
Terminal Half life = 42 hours
Clearance 65-100 L/h
Note: Due to auto inhibition of CYP 3A following repeated dosing mean
apparent clearance may be lower at steady state.
Ethnicity Steady state C-max and AUC were ~1.5-1.6 fold higher in Asians than non-
Asians

MECHANISM OF RESISTANCE
Acquired resistance usually occurs within one year of commencing crizotinib [2]. ALK
mutations have been implicated in a third of resistant tumours [6]. Commonly the resistance
mechanism is due to secondary mutations in the ALK kinase domain. The most frequent
mutations are L1196M, G1269A and C1156Y [7].
Amplification of the rearranged ALK fusion gene is another known mechanism of
resistance [7]. Aberrant activation of other kinases including KIT gene amplification and
increased autophosphorylation of epidermal growth factor receptor have also been identified
as bypass mechanisms [8]. A small minority of people are thought to possible have an
intrinsic resistance.
Several strategies that could possibly delay or overcome crizotinib resistance include
alternate dosing schedules, next generation tyrosine kinase inhibitors e.g., ceritinib, HSP 90
inhibitors and combinations of ALK TKI with other drugs [7].

INDICATIONS
Treatment with crizotinib is indicated in patients who have an advanced or metastatic
NSCLC that contains the ALK fusion oncogene.
116 V. Wood

Before commencing treatment a well-validated and robust method for detecting ALK
mutation should be used such as fluorescence in situ hybridization (FISH) or
immunochemistry.

DOSAGE
Crizotinib should be taken at a dose of 250 mg twice a day orally continuously [1].
If a dose is missed provided it is not within 6 hours of the next dose, it should be taken as
soon as possible. If it is within 6 hours of the next dose then need to wait for the next dose
[1].

METHODS OF PREPARATION/ADMINISTRATION
Crizotinib has an oral route of administration. The gelatine capsules should be taken
whole preferably with water and should not be crushed, dissolved or opened [1]. They can be
taken with or without food. Grapefruit or grapefruit juice should be avoided as it may increase
crizotinib concentration through inhibition of CYP3A.
Crizotinib should be stored at room temperature.

SPECIAL INFORMATION AND CAUTIONS


Contraindications

Hypersensitivity to crizotinib or to any of the excipients listed below:

 Capsule content
 Silica, colloidal anhydrous
 Cellulose, microcrystalline
 Gelatin
 Calcium hydrogen phosphate, anhydrous
 Sodium starch glycolate (Type A)
 Capsule shell
 Titanium dioxide (E171)
 Red iron oxide (E172)
 Printing ink
 Shellac
 Propylene glycol
 Potassium hydroxide
 Black iron oxide (E172)
 Magnesium stearate
 Severe hepatic impairment
Crizotinib. Xalkori® 117

Elderly Patients

No overall differences in safety or efficacy have been observed in patients older than 65
in comparison with younger patients.
No patients in the crizotinib arm of randomised Phase 3 were 85 years or older.

Paediatric Patients

There are no data about safety and efficacy in paediatric patients.

Renal Impairment

In mild to moderate impairment (CrCl ≥ 30 mL/min) no adjustment is required [1].


In severe impairment (CrCl < 30 mL/min), not requiring dialysis a dose reduction of 50%
(i.e., to 250mg once daily) is suggested [1]. The dose may be escalated to 200 mg twice daily
after at least 4 weeks of treatment based on individual tolerability.
There is no published data regarding use of crizotinib in dialysis however the
physiochemical characteristics of the drug suggest that drug removal is unlikely during
dialysis [1].

Hepatic Impairment

There is no information found for starting doses. Crizotinib is extensively metabolized in


the liver so hepatic impairment may result in higher plasma concentrations, although it has
not been specifically studied. In the clinical trials conducted with crizotinib, patients with an
ALT or AST >2.5 x upper limit of normal (ULN) or if due to underlying malignancy >5 ULN
or with a bilirubin >1.5 were excluded [1].

Immunisations

Live vaccines should not be applied while taking the treatment or for at least 6 months
afterwards. Other vaccines can be administered, though may not give as much protection as
usual.
In any case, it is safe to be in contact with other people who have had live vaccines as
injections. There can be problems with oral vaccines. Any contacts with someone who has
had oral polio, cholera or typhoid vaccination recently, should be avoided.

Radiation

There is no known information about the effects of radiation on crizotinib.


118 V. Wood

WARNINGS
Hepatic Laboratory Abnormalities

Elevations in ALT and total bilirubin have occurred.


Monitor monthly and as clinically indicated with more frequent testing in patients with
Grade 2-4 elevations.

QT Interval Prolongation

Baseline electrocardiogram (ECG) and electrolytes should be obtained prior to


commencing treatment. In patients with pre-existing bradycardia, or who have a history or
pre-disposition for QTc prolongation, crizotinib should be used with caution [1].
Periodic monitoring with ECG and electrolytes is recommended.
If QTc increases by ≥60 msec from baseline but is < 500 msec, Crizotinib should be
withheld and cardiology advice sought [1].
If QTc increases ≥500 msec then cardiology advice should be urgently sought [1].
Drugs that prolong QTc interval or disrupt electrolyte levels should be avoided if possible
during treatment with crizotinib due to the risk of potentially fatal arrhythmias [5].

Bradycardia

Heart rate and blood pressure should be regularly monitored.


The full effect of crizotinib on reduction of heart rate may not develop until several
weeks after start of treatment. Avoid using crizotinib in combination with other bradycardic
agents.

Pneumonitis

Severe, including fatal, treatment-related pneumonitis has been observed. Monitor


patients for pulmonary symptoms indicative of pneumonitis. Permanently discontinue in
patients diagnosed with treatment-related pneumonitis.

ALK Testing

Detection of ALK-positive NSCLC using an FDA approved test, indicated for this use, is
necessary for selection of patients for treatment with crizotinib.
Crizotinib. Xalkori® 119

Pregnancy, Breast-Feeding, Fertility

Crizotinib can cause fetal harm when administered to a pregnant woman. Adequate
contraceptive methods should be used during therapy, and for at least 90 days after
completing therapy.
It is not known whether crizotinib and its metabolites are excreted in human milk but
because of the potential harm it is advised to avoid breast-feeding while receiving it.
Male and female fertility may be compromised thus advice on fertility preservation
before treatment should be sought.

Vision Disorders

Patients experiencing vision disorders on crizotinib should be cautious when driving or


operating machinery.

TOXICITIES [1, 9]
They are derived from the phase 3 PROFILE 1007 trial as reported for the crizotinib arm.
In this trial permanent discontinuation from crizotinib occurred in 6% of patients due to
treatment related adverse events.

System Organ Very Common Common Uncommon


Class ≥1/10 ≥1/1000 to <1/10 ≥1/1,000 to <1/1000
Cardiovascular Chest pain or QTc prolongation
discomfort Bradycardia
Syncope
Blood and Anaemia Leukopenia
lymphatic Neutropenia
Metabolism and Decreased Appetite Hypophosphataemia
Nutrition Dysgeusia
Respiratory Dyspnea Interstitial Lung Disease
Cough
Eye Vision disorder*
(including diplopia,
blurry vision and
vitreous floaters)
Nervous System Dizziness
Neuropathy
Headache Dysgeusia
Gastrointestinal Diarrhoea Dyspepsia Gastrointestinal
Nausea Perforation
Vomiting Constipation
Hepatobiliary Elevated Transaminases Blood alkaline phosphatase Hepatic Failure
increased
Skin Rash
Alopecia
120 V. Wood

Table. (Continued)

System Organ Very Common Common Uncommon


Class ≥1/10 ≥1/1000 to <1/10 ≥1/1,000 to <1/1000
Renal and urinary Renal Cyst
General Oedema
Fatigue
Musculoskeletal Arthralgia
disorders Back pain
Psychiatric Insomnia
Others
Hypogonadism
A rapid reduction in testosterone levels has been observed within 14-21 days of crizotinib treatment [13].
A study noted reduced testosterone levels in 84% of men on crizotinib [13]. 80% of these men had
symptoms associated such as sexual dysfunction or depression [13]. Therefore the potential for
hypogonadism should be discussed with male patients before commencing treatment.
Testosterone replacement should be considered if needed.
*
Vision disorders have been reported in 60% of patients on crizotinib [5]. More than 95% of these were
considered mild in terms of severity [5]. The median time to onset is 7-13 days and it often improves
with length of time on treatment [5]. Symptoms have rarely required interruption/cessation. If the vision
disorder is severe, persists or worsens an ophthalmology opinion should be sought [5].

DOSE MODIFICATIONS [1]


The dosage of crizotinib may be reduced, delayed or discontinued in patients who
experience toxicity.

 Hematologic (neutropenia and leukopenia)

Grade (CTCAE) Dose modification


Grade 3 Withhold until ≤ grade 2 and then resume at the same dose schedule
Grade 4 Withhold until recovery to grade 2, then resume at 200mg twice daily

 Transaminasitis

Transaminasitis Grade (CTCAE) Dose modification


Raised ALT or AST with normal Bilirubin Grade 3 or 4
Raised ALT or AST with concurrent Grade 2,3 or 4 Permanently discontinue
elevation of bilirubin

 Insterstitial lung disease (ILD/pneumonitis)

Grade (CTCAE) Dose modification


Any grade Withhold if suspected and permanently discontinue if treatment-related
ILD/pneumonitis is diagnosed

 QTc prolongation
Crizotinib. Xalkori® 121

Grade (CTCAE) Dose modification


Grade 3 Withhold until recovery to grade ≤1, check and if necessary correct
electrolytes, and then resume at 200mg twice daily
Grade 4 Permanently discontinue

 Bradycardia

Grade (CTCAE) Dose modification


Grade 2 or 3 Withhold until recovery to grade ≤ 1 or to heart rate 60 or above.
Evaluate if concomitant medications known to cause bradycardia are
contributing (e.g., Beta blockers)
If so then to either discontinue or reduce dose of concomitant
medication, and resume crizotinib to previous dose once recovery to
grade ≤ 1 or heart rate 60 or above
Grade 4 Permanently discontinue if no contributory concomitant medication is
identified.
If contributing concomitant medication is identified and discontinued,
or its dose adjusted, resume at 250mg once daily upon recovery to
grade ≤ 1 or to heart rate 60 or above with frequent monitoring.
Note: In the event of further recurrence of grade ≥ 3 bradycardia
crizotinib should be permanently discontinued
Asymptomatic Not required dose modification

INTERACTIONS [5]
Co-administration of strong inhibitors and inducers of CYP3A should be avoided, as
should CYP3A4 substrates with narrow therapeutic indices [1].
Crizotinib use should also be avoided in combination with other bradycardic agents or
medications that are known to prolong QTc interval and/or anti arrhythmics. Further drug
interactions are listed below.

Agent Mechanism Effect Management


Esomeprazole pH dependent Not considered Starting dose adjustment is not
solubility; reduced clinically significant required during concurrent therapy
crizotinib with with proton pump inhibitors, H2
increasing pH blockers or antacids.
Grapefruit May inhibit CYP 3A4 May increase plasma Avoid grapefruit and grapefruit
juice metabolism of level of crizotinib. juice for duration of treatment with
crizotinib in the crizotinib.
intestinal wall
Midazolam Moderate inhibition of 3.7 fold increase in Monitor for signs of toxicity due to
CYP 3A by crizotinib midazolam AUC midazolam
Rifampicin Strong induction of 82% decrease in Avoid concurrent administration of
CYP 3A4 crizotinib AUC; 69% possible.
decrease in crizotinib
Cmax.
Ketoconazole Strong inhibition of 3-fold increase in Avoid concurrent administration of
CYP 3A4 by crizotinib AUC; 1.4 possible.
ketoconazole fold increase in
crizotinib Cmax.
122 V. Wood

CONCLUSION
Crizotinib is an oral TKI that targets the EML4-ALK fusion protein. It has demonstrated
benefit in the 1st and 2nd line setting for the treatment of NSCLC that express the ALK gene
rearrangement. It is generally well tolerated with most related adverse events being mild to
moderate in severity, and with appropriate monitoring and supportive treatment, the need for
dose modification is reduced [11].

REFERENCES
[1] Ema.europa.eu. [Internet]. 2015 [cited May 2015]. Available from: http://
www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_
Information/human/002489/WC500134759.pdf.
[2] Sahu K, Prabhash K, Noronha V, Joshi A, Desai S. Crizotinib: A comprehensive
review. South Asian Journal of Cancer. 2013 Apr;2(2):91-97.
[3] Shaw AT, Kim DW, Nakagawa K, Seto T, Crinó L, Ahn MJ, et al. Crizotinib versus
chemotherapy in advanced ALK-positive lung cancer. New England Journal of
Medicine. 2013 Jun;368(25):2385-2394.
[4] Uptodate.com. Anaplastic lymphoma kinase (ALK) fusion oncogene positive non-small
cell lung cancer [Internet]. 2015 [cited May 2015]. Available from: http://www.
uptodate.com/contents/anaplastic-lymphoma-kinase-alk-fusion-oncogene-positive-non-
small-cell-lung-cancer.
[5] Lee c. http://www.bccancer.bc.ca/chemotherapy-protocols-site/Documents/Lung/
ULUAVCRIZ_Protocol_1Dec2015.pdf. 1st ed. 2015 [Cited May 2015].
[6] Yamaguchi N, Lucena-Araujo AR, Nakayama S, de Figueiredo-Pontes LL, Gonzalez
DA, Yasuda H. Dual ALK and EGFR inhibition targets a mechanism of acquired
resistance to the tyrosine kinase inhibitor in ALK rearranged lung cancer. Lung Cancer.
2014 Jan;83(1):37-34.
[7] Awad MM, Shaw AT. ALK inhibitors in non-small cell lung cancer: Crizotinib and
beyond. Clin Adv in Hematol Oncol. 2014 Jul;12(7):429-39.
[8] Lovly CM, Pao W 2012. Escaping ALK inhibition: Mechanisms of and strategies to
overcome resistance. Sci Transl Med 4: 120ps2.
[9] Solomon BJ, Mok T, Kim DW, Wu YL, Nakagawa K, Mekhail T, Felip E, Cappuzzo F,
Paolini J, Usari T, Iyer S, Reisman A, Wilner KD, Tursi J, Blackhall F. First line
Crizotinib versus chemotherapy in ALK positive lung cancer. New England Journal of
Medicine. 2014; 371:2167-2177.
[10] Shaw AT, Kim DW, Nakagawa K, Seto T, Crinó L, Ahn MJ, De Pas T, Besse B,
Solomon BJ, Blackhall F, Wu YL, Thomas M, O'Byrne KJ, Moro-Sibilot D, Camidge
DR, Mok T, Hirsh V, Riely GJ, Iyer S, Tassell V, Polli A, Wilner KD, Jänne
PA.Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. New
England Journal of Medicine. 2013; 368(25) 2385-94.
[11] Cappuzzo F, Moro-Sibilot D, Gautschi O, Boleti E, Felip E, Groen HJ, Germonpré P,
Meldgaard P, Arriola E, Steele N, Fox J, Schnell P, Engelsberg A, Wolf J Management
of Crizotinib therapy for ALK-rearranged non-small cell lung carcinoma: An expert
consensus. Lung Cancer. 2015,87(2) 89-95.
In: The Easy Book of Cancer Pharmacology ISBN: 978-1-63485-038-4
Editor: Esther Una Cidon © 2016 Nova Science Publishers, Inc.

Chapter 14

CYTARABINE: ARA-C: CYTOSAR U:


CYTOSINE ARABINOSIDE: TARABINE PFS,
ARABINOSYLCYTOSINE, 1-Β-ARABINOSYLCYTOSINE

T. Cummin
Haematology Department, Poole Hospital NHS Foundation Trust, Poole, UK

ABSTRACT
Cytarabine is a parenterally administered chemotherapeutic drug currently used in
the treatment of a number of haematological malignancies, namely acute leukaemias and
some lymphomas. It is an anti-metabolite which is metabolised in the liver and
predominantly excreted in the urine.
Cytarabine can be used as a single agent or in combination with other drugs such as
daunorubicin. It can be used in a number of applications including high-dose therapy,
conditioning for stem-cell transplants, intra-thecal and lower-dose treatment.
Myelosuppression commonly occurs and patients may require blood product support and
prompt treatment for infections including neutropenic sepsis particularly at higher doses.
Other common side effects include gastro-intestinal disturbances, renal impairment and
transaminitis.

Keywords: cytarabine, cytosine arabinoside

INTRODUCTION
Cytarabine is an anti-metabolite commonly used in the treatment of leukaemia and
lymphoma. It can be given via the intravenous, subcutaneous or intra-thecal routes. It is used
as a single agent or in combination with other drugs such as daunorubicin. It can be used in a
number of applications including high-dose therapy, conditioning for stem-cell transplants,
intra-thecal and low-dose treatment [1-4].


Thomas Cummin, tcummin@gmail.com.
124 T. Cummin

Myelosuppression commonly occurs and patients may require blood product support and
prompt treatment for infections including neutropenic sepsis particularly at higher doses.
Other common side effects include gastro-intestinal disturbances, renal impairment and
transaminitis [1-4].

CLINICAL PHARMACOLOGY
Drug Classification

Cytarabine is an anti-metabolite/synthetic pyrimadine nucleoside [1-3].

Mechanism of Action

Cytarabine is a synthetic pyrimadine nucleoside. Cytarabine requires intracellular


activation from the naturally occurring deoxycytidine analog to ara-CTP, the active
metabolite. The primary activity of cytarabine is during S-phase, in cells undergoing DNA
synthesis. It may also block progression of cells from G1 phase to S-phase. Ara-CTP is
incorporated into DNA during replication leading to strand termination. It interferes with
DNA synthesis, repair and chain elongation by inhibiting DNA polymerase [4, 5].

Pharmacokinetics [4, 5, 6]

Absorption Cytarabine must be administered parenterally due to poor bioavailability via the
oral route. It is usually given intravenously but is also administered by the
subcutaneous route. It can be given intrathecally for treatment of the central
nervous system (CNS).
Systemic Exposure after IT is negligible
Peak Plasma Time: 20-60 min
Peak CSF Time (IT): 60 min
Peak CSF Concentration (IT): 30-50 mcg/mL
Distribution The drug rapidly distributes amongst tissues. Cytarabine has good CNS
penetrance by crossing the blood-brain-barrier.
Protein bound 13%
Metabolism Cytarabine undergoes intracellular conversion to it is active metabolite, ara-CTP.
Ara-CTB undergoes deamination in the liver, plasma and other tissues to it is
inactive metabolite by cytadine deaminase.
Excretion The liver rapidly metabolises cytarabine to the inactive metabolite
1-β-D-arabinofuranosyluracil.
Within 24 hours 70-80% of a dose is excreted in the urine.
Half-Life: 1-3 hr Half-Life (CSF after IT): 5.9-82.4 hr CSF clearance rate: 0.24
mL/min
Cytarabine 125

Indications [1-4]

Acute myeloid leukaemia, erythroleukaemia, acute lymphoblastic leukaemia and blast-


phase chronic myeloid leukaemia.
Intra-thecal prophylaxis and treatment for meningeal leukaemia and lymphoma.
Lymphoma such as primary central-nervous system lymphoma and mantle-cell
lymphoma. Also, as part of conditioning for stem cell transplants for haematological
malignancies.

Dosages [1, 3, 6]

Typical induction dose for AML usually as part of DA regime for 8 or 10 days:
100mg/m2 iv every 12 hours.
Consolidation for AML usually on days 1, 3 and 5 in under 60 year olds: 3000mg/m2 iv
every 12 hours.
Consolidation for AML: usually on days 1, 3 and 5 in over 60 year olds: 1000mg/m2 iv
every 12 hours.
Dosages vary for relapsed/refractory AML or in stem cell transplant patients
2000mg/m2 iv every 12 hours (for treatment of primary central nervous system
lymphoma with high-dose methotrexate)
As part of BEAM, autograft stem cell transplant conditioning 200-400mg/m2 iv
20mg sc every 12 hours (usually for elderly AML every 4-6 weeks)
5mg/m2 to 75mg/m2 intrathecally have been used, should not exceed 100mg total daily
dose (must be preservative-free only)

Methods of Preparation/Administration [1-4]

Reconstituted from a powder usually to a concentration of 20mg/ml or 100mg/ml. Also


comes as a 100mg/ml ready to use injection.
Intravenous cytarabine is usually administered over 1-3 hours or as a continuous (24
hour) infusion.
Subcutaneous cytarabine is usually given into the thigh or abdomen.
For intra-thecal use cytarabine hydrochloride powder is used and diluted with an
unpreserved diluent. It must be administered by a registered professional. Pre-prepared
cytarabine injection is hypertonic and should not be used for intra-thecal use [6].

Special Information and Cautions

Contraindications
Hypersensitivity to the drug or its excipients.
126 T. Cummin

Elderly
Dose should be lower as higher risk of toxicities.

Pediatric
Conventional drug is recommended as in adults and not recommended the liposomal.

Renal Impairment
As exposed in ―
Dose modifications‖ section.

Hepatic Impairment
As exposed in ―
Dose modifications‖ section.

Immunisations
Live vaccines should not be applied while taking the treatment or for at least 6 months
afterwards. Other vaccines can be administered, though may not give as much protection as
usual. In any case, it is safe to be in contact with other people who have had live vaccines as
injections. There can be problems with oral vaccines. Any contacts with someone who has
had oral polio, cholera or typhoid vaccination recently, should be avoided.

Pregnancy
It can cause fetal harm. Therefore effective methods of contraception are needed.

Breast-Feeding
It is unknown if this drug is excreted in human milk, thus nursing is not advisable.

Warnings

Myelosuppression
It is common with a nadir of 7-9 and 15-24 days. During induction or high-dose therapy
blood counts should be monitored regularly as patients often require blood product and
antimicrobial support. Hemorrhage from thrombocytopenia, life-threatening infections with
neutropenia and bone marrow failure can occur [1].

Cytarabine Syndrome
It involves fever, myalgia, bone pain, occasionally chest pain, exanthema, maculopapular
rash, conjunctivits, nausea and malaise. It tends to occur 6-12 hours after administration.
Corticosteroids have been beneficial in treating and preventing the syndrome [1].
Corticosteroid eye drops should be used as prophylaxis for high-dose therapy.
Cytarabine 127

Toxicities [1, 6]

Organic system disorder Common ≥1/1000 to <1/10 Uncommon ≥1/1,000 to <1/1000


Respiratory disorders Pneumonia, dyspnea, sore throat
Metabolism and nutrition Anorexia, hyperuricaemia
disorders
Nervous system Dysarthria, nystagmus, at high Headache, peripheral neuropathy,
disorders doses cerebellar or cerebral paraplegia at intra-thecal
effects administration
Blood and lymphatic Anaemia, megaloblastosis,
system disorders leucopenia, thrombocytopenia
Renal and urinary Renal impairment, urinary
disorders retention
Gastrointestinal Nausea and vomiting, diarrhea, Oesophagitis, oesophageal
disorders dysphagia, oral/anal ulceration, peritonitis, necrotizing
inflammation colitis
Hepatobiliary disorders Reversible increased liver
enzymes
Skin and subcutaneous Erythema, bullous dermatitis, Lentigo, skin ulceration, pruritis,
tissue disorders urticaria, vasculitis, alopecia burning pain palms and soles
Cardiovascular disorders Pericarditis
Musculoskeletal disorders Myalgia, joint pain
Eye disorders Reversible hemorrhagic
conjunctivitis, keratitis
Very rare
Neutrophilic eccrine hidradenitis
Unknown
Reticulocytopenia
GI haemorrhage
Pancreatitis
Rash
Freckling
Skin bleeding
Renal dysfunction
Arrythmia
Hepatitic dysfunction and jaundice
One case of anaphylaxis and cardiac arrest reported
Dizziness, neuritis or neural toxicity and pain, neurotoxicity
Conjunctivitis

Adverse Effect Due to High-Dose Cytarabine [1]

Blood and lymphatic systems


Profound pancytopenia may occur which may last 15-25 days. It is more severe than in
conventional doses
128 T. Cummin

(Continued)

Nervous system
Symptoms of cerebral or cerebellar influence like personality changes, affected alertness,
dysarthria, ataxia, tremor, nystagmus, headache, confusion, somnolence, dizziness, coma,
convulsions, etc. may occur.
These are found in 8-37% of treated patients. The elderly are more susceptible. In most cases
these are reversible. Risk is higher if given in conjunction with CNS toxic treatments such as
radiotherapy or other cytotoxic agents
Eyes
Corticosteroid eye drops should be prescribed to prevent corneal lesions and hemorrhagic
conjunctivitis.
Gastro-intestinal
Pancreatitis, peritonitis, intestinal perforation and necrosis.
Hepatobiliary
Budd-Chiari, liver abscesses and hepatomegaly.
Respiratory
Acute Respiratory Distress Syndrome (ARDS)
Reproductive
Azoospermia and amenorrhoea
Others
Cardiomyopathy and rhabdomyolysis

Dose Modifications

Cytopenias usually necessitate delaying chemotherapy until recovery.

Renal Impairment in High-Dose Cytarabine [3]

Creatinine clearance (mL/min) % dose


>60 100% dose
46-60 60% dose
31-45 50% dose
<30 Clinician‘s decision

Hepatic Impairment in High-Dose Cytarabine [3]

Bilirubin (mml/L) % dose


<34 100% dose
>34 50% dose

Low-Dose Cytarabine [5]


Courses commence from hematopoietic recovery i.e., neutrophils >0.9 and platelets >99.
Therapy may continue below these levels at the clinicians discretion if myelosuppression is a
symptom of disease burden.
Cytarabine 129

Interactions [1, 3, 6]

5-Fluorocytosine: cytarabine can act antagonistically and reduce the efficacy of this anti-
fungal.
Cyclophosphamide: use in conjunction with cytarabine has resulted in cardiomyopathy.
Methotrexate: cytarabine can inhibit cellular uptake of methotrexate. Methotrexate may
decrease the cellular activation of cytarabine.
L-Asparaginase: it increases the risk of pancreatitis if this one is given before cytarabine.
Bone Marrow Suppressants: can have an additive effect with cytarabine [6].
Digoxin: cytarabine reduces the oral bioavailability of digoxin, thereby reduces its
efficacy. Monitor levels while on therapy.
Gentamycin: Cytarabine antagonizes the efficacy of gentamicin.

CONCLUSION
Cytarabine is a well-established anti-metabolite in the treatment of hematological
malignancies and is a cornerstone in many regimes or used as a single-agent. This includes
low-dose treatment in elderly AML to high-dose therapy including conditioning for stem cell
transplant. The most common side effects are predictable hematological toxicity which
requires intensive supportive therapy.

REFERENCES
[1] https://www.medicines.org.uk/emc/medicine/8266.
[2] http://chemocare.com/chemotherapy/drug-info/cytarabine.aspx#. VQYAQE InSA4.
[3] http://www.londoncanceralliance.nhs.uk/media/36431/aml_hidac__protocol_v1.0.pdf.
[4] http://www.lwwoncology.com/Textbook/Content.aspx?aid=9835458.
[5] West London Cancer Network. Treatment of Chemotherapy induced nausea and
vomiting prescribing guidelines. May 2002.
[6] http://www.medsafe.govt.nz/profs/datasheet/c/Cytarabinenjmp.pdf.
In: The Easy Book of Cancer Pharmacology ISBN: 978-1-63485-038-4
Editor: Esther Una Cidon © 2016 Nova Science Publishers, Inc.

Chapter 15

DENOSUMAB, PROLIA®, XGEVA®

P. Alonso* and P. Diezhandino


Radiotherapy Oncology Service, Clinical University Hospital,
Valladolid, Spain

ABSTRACT
Denosumab, a fully human monoclonal antibody which binds the receptor activator
of nuclear factor-κ B ligand (RANKL) is a novel agent, that inhibits osteoclastic-
medicated bone resorption by binding to osteoblast-produced RANKL. By reducing
RANKL binding to the osteoclast receptor RANK, bone resorption and turnover
decrease.
In phase 2 dose-ranging studies, denosumab had a rapid onset and offset effect. Also,
in patients who had received 2 years of denosumab and were discontinued for the third
year, rechallenge with denosumab during the fourth year demonstrated a return of
responsiveness to denosumab that mimicked the initial treatment. Phase 3 pivotal fracture
data were recently presented with positive outcome data; denosumab (60 mg
subcutaneously every 6 months) significantly reduced vertebral, non-vertebral, and hip
fracture risk compared with placebo, and had an excellent safety profile through 3 years
of use [1].

Keywords: denosumab, RANKL

INTRODUCTION
Antiresorptive drugs (e.g., bisphosphonates, oestrogen, denosumab) reduce bone turnover
by different mechanisms. Denosumab is a fully human monoclonal antibody that binds the
cytokine RANKL (receptor activator of NFκB ligand), an essential factor initiating bone
turnover.

*
E-mail: pi_villita@hotmail.com.
132 P. Alonso and P. Diezhandino

This inhibition blocks osteoclast maturation, function and survival, leading to a reduction
in bone resorption.
Denosumab has got a rapid onset and offset effect and studies have shown positive results
in osteoporosis and several tumors with bone involvement by increasing bone mineral density
and reducing the incidence of bone fractures.

CLINICAL PHARMACOLOGY
Drug Classification

Denosumab is a monoclonal antibody with affinity for the RANKL.

Mechanism of Action

Denosumab is a monoclonal antibody with affinity for RANKL. Osteoblasts secrete


RANKL and this activates osteoclast precursors and subsequent osteolysis which promotes
release of bone-derived growth factors, such as insulin-like growth factor-1 (IGF1) and
transforming growth factor-beta (TGF-beta), and increases serum calcium levels.
Denosumab binds to RANKL, blocks the interaction between RANKL and RANK (a
receptor located on osteoclast surfaces), and prevents osteoclast formation, leading to
decreased bone resorption and increased bone mass in osteoporosis.
In solid tumors with bony metastases, RANKL inhibition decreases osteoclastic activity
leading to decreased skeletal related events and tumor-induced bone destruction.
In giant cell tumors of the bone (which express RANK and RANKL), denosumab inhibits
tumor growth by preventing RANKL from activating its receptor (RANK) on the osteoclast
surface, osteoclast precursors, and osteoclast-like giant cells [1, 2].

Pharmacokinetics

Absortion Subcutaneous administration, bioavailability of 62%


Distribution Similar to plasma volume

Metabolism Not applicable (as a protein it should end up in aminoacides)


Excretion Half-life of approximately 25-30 d. Dose-dependent, non linear
elimination

Mechanism of Resistance

Not applicable.
Denosumab, Prolia®, Xgeva® 133

Indications [3, 4, 5]

NOTE: Administer calcium and vitamin D as necessary to prevent or treat hypocalcemia

 Hypercalcemia of malignancy
120 mg every 4 weeks; during the first month, give an additional 120 mg on days 8
and 15.
 Prevention of skeletal-related events in bone metastases from solid tumors
120 mg every 4 weeks.
 Treatment of androgen deprivation-induced bone loss in men with prostate cancer
60 mg as a single dose, once every 6 months.
 Treatment of aromatase inhibitor-induced bone loss in women with breast cancer
60 mg as a single dose, once every 6 months.
 Treatment of giant cell tumor of the bone
120 mg once every 4 weeks; during the first month, give an additional 120 mg on
days 8 and 15.
 Treatment of osteoporosis in men or postmenopausal women
60 mg as a single dose, once every 6 months

NOTE

 Breast cancer
The American Society of Clinical Oncology (ASCO) updated guidelines on the role
of bone-modifying agents (BMAs) in the prevention and treatment of skeletal-related
events for metastatic breast cancer patients (Van Poznak 2011).
The guidelines recommend initiating a BMA (denosumab, pamidronate, zoledronic
acid) in patients with metastatic breast cancer to the bone. There is currently no
literature indicating the superiority of one particular BMA.
Optimal duration is not defined; however, the guidelines recommend continuing
therapy until substantial decline in patient‘s performance status. The ASCO
guidelines are in alignment with package insert guidelines for dosing, renal dose
adjustments, infusion times, prevention and management of osteonecrosis of the jaw,
and monitoring of laboratory parameter recommendations.
BMAs are not the first-line therapy for pain. BMAs are to be used as adjunctive
therapy for cancer-related bone pain associated with bone metastasis, demonstrating
a modest pain control benefit. BMAs should be used in conjunction with agents such
as NSAIDs, opioid and non-opioid analgesics, corticosteroids, radiation/surgery, and
interventional procedures.
 Multiple myeloma
Denosumab is not indicated for the prevention of SRE in patients with multiple
myeloma. In trials of multiple myeloma patients, denosumab was non-inferior to
zoledronic acid in delaying time to first SRE and mortality was increased in a subset
of the denosumab-treated group.
134 P. Alonso and P. Diezhandino

Dosage [2]

See Indications section

Methods of Preparation/Administration [2]

Denosumab is intended for subcutaneous route only and should not be administered
intravenously, intramuscularly, or intradermally.
Prior to administration, bring to room temperature in original container (allow to stand
~15 to 30 minutes); do not warm by any other method.
Solution may contain trace amounts of translucent to white protein particles; do not use if
cloudy, discolored (normal solution should be clear and colorless to pale yellow), or contains
excessive particles or foreign matter.
Avoid vigorous shaking. Administer via subcutaneous injection in the upper arm, upper
thigh, or abdomen.
Prolia®: If a dose is missed, administer as soon as possible, then continue dosing every 6
months from the date of the last injection.

Special Information and Cautions

Contraindications
Hypersensitivity to denosumab or any component of the formulation
Preexisting hypocalcemia
Pregnancy (Prolia only)

Elderly Patients
No pharmacokinetic influences seen.

Pediatric Patients
No pharmacokinetic data available.

Renal Impairment
Use with caution in patients with renal impairment (CrCl <30 mL/minute) or patients on
dialysis; risk of hypocalcemia is increased.
Dose adjustment is not needed when administered at 60 mg every 6 months (Prolia).
Once-monthly dosing has not been evaluated in patients with renal impairment (Xgeva).
Adequate intake of calcium and vitamin D is more relevant in patients with renal
insufficiency. In those an increase in PTH has been observed.

Hepatic Impairment
No pharmacokinetic data available.
Denosumab, Prolia®, Xgeva® 135

Pregnancy
Recommended an anticonceptive method to avoid pregnancy.

Warnings [2]

Bone Fractures
Atypical femur fractures have been reported in patients receiving denosumab. The
fractures may occur anywhere along the femoral shaft (may be bilateral) and commonly occur
with minimal or no trauma to the area.
Some patients experience prodromal pain weeks or months before the fracture occurs.
Because these fractures also occur in osteoporosis patients not treated with denosumab, it is
unclear if denosumab therapy is the cause for the fractures; concomitant glucocorticoids may
contribute to fracture risk.
Advise patients to report new/unusual hip, thigh, or groin pain; and if so, evaluate for
atypical/incomplete fracture. Contralateral limb should be assessed if atypical fracture occurs.
Consider interrupting therapy in patients who develop an atypical femoral fracture.

Dermatologic Reactions
Dermatitis, eczema, and rash (which are not necessarily specific to the injection site)
have been reported. Consider discontinuing if severe symptoms occur.

Hypersensitivity
Clinically significant hypersensitivity (including anaphylaxis) has been reported. May
include throat tightness, facial edema, upper airway edema, lip swelling, dyspnea, pruritus,
rash, urticaria, and hypotension.
If anaphylaxis or clinically significant hypersensitivity occurs, initiate appropriate
management and permanently discontinue.

Hypocalcemia
Denosumab may cause or exacerbate hypocalcemia; severe symptomatic cases (including
fatalities) have been reported.
An increased risk has been observed with increasing renal dysfunction, most commonly
severe dysfunction (creatinine clearance (CrCl) <30 mL/minute and/or on dialysis), and with
inadequate/no calcium supplementation.
Monitor calcium levels; correct preexisting hypocalcemia prior to therapy. Monitor levels
more frequently when denosumab is administered with other drugs that can also lower
calcium levels. Use caution in patients with a history of hypoparathyroidism, thyroid surgery,
parathyroid surgery, malabsorption syndromes, excision of small intestine, severe renal
impairment/dialysis, or other conditions which would predispose the patient to hypocalcemia;
Monitor calcium, phosphorus, and magnesium closely during therapy.
Administer calcium, vitamin D, and magnesium as necessary.
Patients with severe renal impairment (CrCl <30 mL/minute) or those on dialysis may
also develop marked elevations of serum parathyroid hormone (PTH).
136 P. Alonso and P. Diezhandino

Infection
Incidence of infections may be increased, including serious skin infections, abdominal,
urinary, ear, or periodontal infections.
Endocarditis has also been reported following use.
Patients should be advised to contact their healthcare provider if signs or symptoms of
severe infection or cellulitis develop.
Use with caution in patients with impaired immune systems or using concomitant
immunosuppressive therapy; may be at increased risk for serious infections. Evaluate the
need for continued treatment with serious infection.

Osteonecrosis of the Jaw (ONJ)


ONJ may manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth/periodontal
infection, toothache, gingival ulceration/erosion.
Risk factors include invasive dental procedures (eg, tooth extraction, dental implants,
boney surgery); a diagnosis of cancer, concomitant chemotherapy or corticosteroids, poor oral
hygiene, ill-fitting dentures; and comorbid disorders (anemia, coagulopathy, infection,
preexisting dental disease).
In studies of patients with osseous metastasis, a longer duration of denosumab exposure
was associated with a higher incidence of ONJ.
Patients should maintain good oral hygiene during treatment. A dental exam and
preventive dentistry should be performed prior to therapy. The benefit/risk must be assessed
by the treating physician and/or dentist/surgeon prior to any invasive dental procedure; avoid
invasive procedures in patients with bone metastases receiving denosumab for prevention of
skeletal-related events.
Patients developing ONJ while on denosumab therapy should receive care by a dentist or
oral surgeon; extensive dental surgery to treat ONJ may exacerbate ONJ; evaluate
individually and consider discontinuing if extensive dental surgery is necessary.

Musculoskeletal Pain
Severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported
(time to onset of symptoms has varied from one day to several months after initiating
therapy). Consider discontinuing use if severe symptoms develop.

Dose Modifications [2]

There are no dose adjustments provided in the manufacter‘s labelling for renal, hepatic
impairment or elderly age.
Denosumab, Prolia®, Xgeva® 137

Toxicities [2]
Organic disorders Very common Common Uncommon Rare
≥1/10 ≥1/100 and <1/10 ≥1/1000 and ≥1/10,000 and
<1/100 <1/1000
Hair and skin Dermatitis, eczema,
disorders skin rash

Vascular disorders Hypertension Hypotension Thrombotic


microangiopathy
Cardiac disorders Angina pectoris Endocarditis

General disorders Fatigue, peripheral Wound healing


edema impaired

Neurological Headache Sciatica


disorders

Gastrointestinal Nausea, decreased Flatulence Pancreatitis


disorders appetite, vomiting,
constipation, diarrhea

Investigations Hypophosphatemia, Hypercholesterolemia


hypocalcemia
Blood and Anemia
lymphatic disorders

Neoplastic disorders Malignant neoplasm


Eye disorders Cataract

Respiratory and Dyspnea, cough Nasopharyngitis, upper


thoracic disorders respiratory tract infection

Musculoskeletal Weakness, arthralgia, Musculoskeletal pain, Femur fracture


disorders back pain, limb pain ostealgia, myalgia, (diaphyseal,
osteonecrosis jaw subtrochanteric)

Infections and Serious infection, upper


infestations respiratory tract infection

Immunological Influenza Antibody


disorders development,
hypersensitivity

Interactions [2]

 Belimumab: Monoclonal Antibodies may enhance the adverse/toxic effect of


Belimumab. Risk X: Avoid combination
 Immunosuppressants: Denosumab may enhance the adverse/toxic effect of
Immunosuppressants. Specifically, the risk for serious infections may be increased.
Exceptions: Cytarabine (Liposomal). Risk C: Monitor therapy
138 P. Alonso and P. Diezhandino

CONCLUSION
Denosumab has documented efficacy and safety in patients with osteoporosis and
oncology. Additional clinical trial data are needed to more completely establish the
effectiveness of denosumab in the treatment of osteoporosis and neoplastic disease as well as
its cost-effectiveness and long-term safety [6].
Denosumab was non-inferior (trending to superiority) to Zolendronic Acid in preventing
or delaying first on-study skeletal-related event (SRE) in patients with advanced cancer
metastatic to bone or myeloma. Denosumab represents a potential novel treatment option with
the convenience of subcutaneous administration and no requirement for renal monitoring or
dose adjustment [7].

REFERENCES
[1] Miller P. D. 1. Denosumab: anti-RANKL antibody. Curr. Osteoporos. Rep., 2009 Mar.;
7(1):18-22.
[2] http://www.fda.gov/Drugs/InformationOnDrugs.
[3] Fizazi K., Carducci M., Smith M., Damião R., Brown J., Karsh L. et al. Denosumab
Versus Zoledronic Acid for Treatment of Bone Metastases in Men With Castration-
Resistant Prostate Cancer: A Randomised, Double-Blind Study. Lancet, 2011;
377(9768):813-22.
[4] Xgeva (denosumab) [prescribing information]. Thousand Oaks, CA: Amgen Inc;
December 2014.
[5] Prolia (denosumab) [prescribing information]. Thousand Oaks, CA: Amgen Inc; June
2014.
[6] Burkiewicz J. S., Scarpace S. L., Bruce S. P. Denosumab in osteoporosis and oncology,
2009 Sep.; 43(9):1445-55. doi: 10.1345/aph.1M102. Epub 2009 Jul 21.
[7] Henry D. H., Costa L., Goldwasser F., Hirsh V., Hungria V., Prausova J. et al.
Randomized, double-blind study of denosumab versus zoledronic acid in the treatment
of bone metastases in patients with advanced cancer (excluding breast and prostate
cancer) or multiple myeloma. J. Clin. Oncol., 2011; 29(9):1125.
In: The Easy Book of Cancer Pharmacology ISBN: 978-1-63485-038-4
Editor: Esther Una Cidon © 2016 Nova Science Publishers, Inc.

Chapter 16

DOCETAXEL.TAXOTERE®

E. Galve1,, V. Arrazubi1, P. Martínez del Prado1


and E. Una Cidon2
1
Medical Oncology Department. Basurto University Hospital.
Bilbao, Spain
2
Department of Medical Oncology. Royal Bournemouth Hospital
NHS Foundation Trust, UK

ABSTRACT
Docetaxel is a taxane with a potent antitumor activity. It promotes microtubule
polymerization and inhibits tubulin depolymerization which results in the inability of
cells to replicate. It has got activity against many tumoral types. The recommended
dosing regimens is between 60-100 mg/m2 administered intravenously (iv) over one hour,
with cycles repeated every three weeks. The most frequent hematologic side effect is
neutropenia and most nonhematologic adverse effects are generally mild to moderate in
severity. Fluid retention is a toxicity which occurs with cumulative dosing. Premedication
regimens with corticosteroids prevent significant hypersensitivity and these also help
reducing skin reactions and fluid retention [1, 2].

Keywords: docetaxel, taxanes, microtubules

INTRODUCTION
Docetaxel is a semisynthetic taxane. This drug binds to beta tubulin, stabilises
microtubules and induces cell-cycle arrest and apoptosis. Docetaxel was first approved for the
treatment of anthracycline-refractory metastatic breast cancer. After that, several randomised
trials have shown improved survival and time to progression, or both in metastatic breast
cancer treated with single-agent docetaxel or docetaxel-based combination regimens. Other


Elena Galve Calvo, elena.galvecalvo@osakidetza.eus.
140 E. Galve, V. Arrazubi, P. Martínez del Prado et al.

randomised clinical trials showed improvement in survival in locally advanced or metastatic


non-small-cell lung cancer (NSCLC). Docetaxel has shown significantly improved overall
survival when it was added to standard hormone therapy in patients with advanced, hormone-
naive prostate cancer and hormone therapy plus radiation therapy in men with high-risk
localized prostate cancer. Adjuvant trials in breast cancer have aslo reported a survival benefit
when docetaxel is combined with anthracycline-based regimens in with high-risk patients
[1, 2].

CLINICAL PHARMACOLOGY
Drug Classification [3-5]

Semisynthetic taxane. Antimicrotubule agent. Derived from the needles of the European
yew tree.

Mechanism of Action [3-4]

It binds tubuline and enhances its polymerization of cellular microtubules. This will
result in disruption of the normal process of microtubules and eventually leads to mitosis
inhibition and stops cells division [1].

Mechanism of Resistance

Mainly mediated by the expression of the MDR phenotype or by microtubule alterations


[6].

Pharmacokinetics [3, 4]

Absorption Pharmacokinetic profile is dose independent. Three-compartment pharmacokinetic


model. Half-lives for the α, β, and γ phases of 4 min, 36 min, and 11.1 hr,
respectively.
Mean total body clearance was 21 L/h/m2.
Distribution Protein bound: >95%
Distribution volume: 80-90 L/m²
Half-life elimination: 11 hr (terminal)
Metabolism Liver (CYP3A4)
Excretion Clearance: 21 L/hr/m²
Faeces 75%; urine 6%
Docetaxel.Taxotere® 141

Indications [3, 4]

Breast Cancer
Single agent for locally advanced or metastatic breast cancer after chemotherapy failure;
and with doxorubicin and cyclophosphamide as adjuvant treatment of operable node-positive
breast cancer

NSCLC
Single agent for locally advanced or metastatic NSCLC after platinum failure. It is also
indicated in combination with cisplatin for unresectable, locally advanced or metastatic
previously untreated.

Hormone Refractory Prostate Cancer


With prednisone in androgen independent (hormone refractory) metastatic prostate
cancer

Gastric Adenocarcinoma
In combination with cisplatin and fluorouracil for untreated, advanced gastric cancer
including the gastroesophageal junction.

Squamous Cell Carcinoma of the Head and Neck Cancer


In combination with cisplatin and fluorouracil for induction treatment of locally advanced
squamous cell carcinoma of the head and neck cancer.

Dosages [3-5]

Metastastic Breast Cancer


60-100 mg/m2 single agent.

Adjuvant Breast Cancer


75 mg/m2 administered 1 hour after doxorubicin and cyclophosphamide every 3 weeks
for 6 cycles.

NSCLC
After platinum therapy failure: 75 mg/m2 single agent.
Chemotherapy-naive: 75 mg/m2 followed by cisplatin.

Prostate Cancer Hormonorefractory


75 mg/m2 with 5 mg prednisone twice a day continuously.

Gastric Cancer
75 mg/m2 followed by cisplatin and fluorouracil 24-hr iv infusion (days 1-5), starting at
end of cisplatin infusion.
142 E. Galve, V. Arrazubi, P. Martínez del Prado et al.

Head and Neck Tumours


75 mg/m2 followed by cisplatin iv and by fluorouracil as a 24-hr iv infusion (days 1-5),
starting at end of cisplatin infusion; for 3-4 cycles.

For All Patients


 Premedicate with oral corticosteroids
 Adjust dose as needed

Methods of Preparation/Administration [3-5]

Dilution for Infusion


The required amount of Docetaxel Injection solution (10 mg docetaxel/mL) should be
injected into a 250 mL infusion bag of either 0.9% Sodium Chloride solution or 5% Dextrose
solution to produce a final concentration of 0.3 to 0.74 mg/mL.
If a dose greater than 200 mg of Docetaxel is required, a larger volume of the infusion
vehicle should be used so that a the maximum concentration of 0.74 mg/mL is respected.
Mix the infusion bag or bottle manually by gentle inversion and rotation in a controlled
manner and avoid foaming. Shaking or vigorous agitation should be avoided during
preparation and transportation to the patient for administration.

Administration
The solution for infusion should be administered iv as a 1-hour infusion under ambient
room temperature below 25ºC (77ºF). Protect from the light.
When administered in combination it should be administered before platinum derivatives
(cisplatin, carboplatin) to limit myelosuppression and to enhance efficacy.

Stability
Docetaxel infusion solution needs to be stored between 2°C and 25°C (36°F and 77°F) to
be stable.

Special Information and Cautions [3-5]

Contraindications
 Hypersensitivity to the drug or to its excipients listed below:

Concentrate Vial
Polysorbate 80
Citric acid.

Solvent Vial
Ethanol 95%
Water for injections.
 Severe hepatic failure as no data available about safety.
Docetaxel.Taxotere® 143

Elderly
Caution as higher risk of toxicities.

Pediatric
Safety and efficacy not established.

Renal
No data on severe renal insufficiency.

Hepatic
Patients with bilirubin > upper normal level (ULN), AST and/or ALT >1.5 x ULN
concomitant with alkaline phosphatase >2.5 x ULN should not receive Docetaxel.

Immunisations
Live vaccines should not be applied while taking the treatment or for at least 6 months
afterwards. Other vaccines can be administered, though may not give as much protection as
usual.
In any case, it is safe to be in contact with other people who have had live vaccines as
injections. There can be problems with oral vaccines. Any contacts with someone who has
had oral polio, cholera or typhoid vaccination recently, should be avoided.

Pregnancy
Paclitaxel has been shown to be clastogenic, teratogenic and fetotoxic and should not be
used in pregnancy. Men should be advised not to father a child while receiving treatment.

Breast-Feeding
It is not known if paclitaxel is excreted in human milk; however, it is recommended that
nursing should be discontinued during therapy.

Warnings [3, 5]

Hypersensitivity Reactions
Anaphylactoid-like reactions have been reported. Premedicate with dexamethasone.
Severe reactions require immediate discontinuation and administration of appropriate therapy.

Severe Fluid Retention


Severe fluid retention may occur despite dexamethasone.

Toxicities [4]

Organic disorders Very common Common Uncommon


(≥ 1/10) (>1/100 to < 1/10) (≥ 1/1000 to < 1/100)
Infections and Sepsis, pneumonia Infections due to neutropenia
infestations grade 4
144 E. Galve, V. Arrazubi, P. Martínez del Prado et al.

(Continued)

Organic disorders Very common Common Uncommon


(≥ 1/10) (>1/100 to < 1/10) (≥ 1/1000 to < 1/100)
Blood and lymphatic Thrombocytopenia
disorders Neutropenia, anemia,
febrile neutropenia
Immunological Hypersensitivity
disorders
Nutritional and Anorexia
metabolic disorders
Nervous system Peripheral sensitive
disorders neuropathy, motor
peripheral neuropathy,
dysgeusia
Cardiac disorders Arrhythmia Cardiac failure
Vascular disorders Hypotension, hypertension,
haemorrhage
Respiratory and Dyspnea
thoracic disorders
Gastrointestinal Constipation, abdominal pain,
disorders Estomatitis, diarrhoea, gastrointestinal haemorrhage Oesophagitis
nausea, vomiting
Skin and hair Alopecia, skin reactions,
disorders nails changes
Musculoskeletal Myalgia Arthralgia
disorders
General disorders Fluid retention, fatigue,
pain Chest pain (non-cardiac
origin), local reaction
Investigations Increase levels of:
disorders Bilirubin, alkaline
phosphatase, AST, ALT

Dose Modifications [4, 5]

Generally dose modifications follow the same pattern related to toxicities grades.
If grade 1, no modification is necessary.
Grade 2, delay until recovery to grade 1 or less and restart at same dose. If repeats, reduce
dose by 20%.
Grade 3, delay until recovery to grade 1 or less and reduce dose by 20%.
Grade 4, stop the treatment, unless neutropenia.

Interactions [3-5]

Docetaxel is a CYP3A4 substrate and its co-administration with CYP3A4 inhibitors will
increase the exposure to docetaxel. It increases by 2.2-fold when co-administered with
Docetaxel.Taxotere® 145

ketoconazole or with protease inhibitors, particularly ritonavir. When this co-administration


cannot be avoided, a dose reduction should be considered.
Other CYP3A4 inhibitors are cyclosporine, erythromycin, clarithromycin, itraconazole
and other proteasome inhibitors. An interaction with carboplatin has been observed and when
combined, carboplatin clearance is a 50% higher than carboplatin monotherapy.

CONCLUSION
Docetaxel is a semisynthetic taxane which binds to beta tubulin, stabilises microtubules
and induces cell-cycle arrest and apoptosis. It improves survival and time to progression in
metastatic breast cancer treated with single-agent docetaxel or docetaxel-based combination
regimens. It has also shown improvement in survival in locally advanced or metastatic
NSCLC and when added to standard hormone therapy in patients with advanced, hormone-
naive prostate cancer and hormone therapy plus radiation therapy in men with high-risk
localized prostate cancer. Adjuvant trials in breast cancer have aslo reported a survival benefit
when docetaxel is combined with anthracycline-based regimens in with high-risk patients
[1, 2].

REFERENCES
[1] Cortes JE, Pazdur R. Docetaxel. J. Clin. Oncol. 1995;13(10):2643-55.
[2] Montero A, Fossella F, Hortobagyi G, Valero V. Docetaxel for treatment of solid
tumours: a systematic review of clinical data. Lancet Oncol. 2005;6(4): 229-39.
[3] Docetaxel. Medscape. http://reference.medscape.com/drug/taxotere-docefrez-docetaxel-
342192.
[4] Taxotere, INN-Docetaxel-Europe. http://www.ema.europa.eu/docs/es_ES/document_
library/EPAR_Product_Information/human/000073/WC500035264.pdf.
[5] Docetaxel label. Food and drug administration. http://www.access data.fda.
gov/drugsatfda_docs/label/2012/201525s002lbl.pdf.
[6] Galletti E, Magnani M, Renzulli ML, Botta M. Paclitaxel and docetaxel resistance:
molecular mechanisms and development of new generation taxanes. Chem. Med. Chem.
2007;2(7): 920-42.
In: The Easy Book of Cancer Pharmacology ISBN: 978-1-63485-038-4
Editor: Esther Una Cidon © 2016 Nova Science Publishers, Inc.

Chapter 17

DOXORUBICIN HYDROCHLORIDE. ADRIAMYCIN

Z. Anwar
Oncology Department, Poole Hospital NHS Foundation Trust, Poole, UK

ABSTRACT
Adriamycin (doxorubicin hydrochloride) is an antineoplastic agent effective against
a wide range of malignant tumours such as breast carcinomas, malignant sarcomas,
bronchogenic carcinoma, and neuroblastoma among others as well as in hematologic
malignancies (malignant lymphomas and acute leukemias). Side-effects with adriamycin
include stomatitis, nausea, vomiting and alopecia which are predictable and reversible.
More relevant are dose-limiting hematologic and cardiac toxicities. The latter is dose-
dependent and limits its long-term use. Previous mediastinal radiation therapy or left
ventricular dysfunction and advanced age increase the risk. Adriamycin-induced
cardiopathy may be prevented by limiting the total dose to 400 to 450 mg/m 2 following
mediastinal radiation and 500 to 550 mg/m2 for patients without other significant risk
factors.

Keywords: doxorubicin, anthracyclines

INTRODUCTION [1, 2]
Doxorubicin (DOX), (along with daunorubicin, idarubicin, and epirubicin), belongs to the
family of anthracyclines. DOX was isolated from a pigment of Streptomyces Peucetius
(bacterium species), and it was introduced in 1969 for cancer treatment. It remains one of the
most effective and widely used chemotherapeutic agents. It is often used in combination
chemotherapy, as a component of various regimens. Doxorubicin has a very wide anti-tumour
spectrum, compared with other anticancer drugs. The most relevant side-effects are dose-
limiting such as hematologic and cardiac toxicities. The latter is dose-dependent and limits its
long-term use. Previous mediastinal radiation therapy or left ventricular dysfunction and


Email: zuneraanwar@hotmail.com.
148 Z. Anwar

advanced age increase the risk. Adriamycin-induced cardiomyopathy may be prevented by


limiting the total dose to 400 to 450 mg/m2 following mediastinal radiation and 500 to 550
mg/m2 for patients without other significant risk factors.

CLINICAL PHARMACOLOGY
Drug Classification

Antineoplastic agent. It is an anthracycline.

Mechanism of Action [2]

 inhibits of DNA, RNA and protein synthesis


 interacts with DNA by intercalation.
 inhibits the enzyme topoisomerase II (which relaxes supercoils in DNA for
transcription).
 stabilizes the topoisomerase II complex after it has broken the DNA chain for
replication, preventing the DNA double helix from being resealed, thereby stopping
replication.
 may also increase free radical production, contributing to its cytotoxicity.

Pharmacokinetics [3]

Absorption It is not stable in gastric acid, not absorbed from the gastrointestinal tract Therefore
administered via the intravenous (iv) route.
Distribution Widely distributed in plasma and tissues. After administration, present in the liver,
lungs, heart, and kidneys. Absorbed by cells and binds to nucleic acids. It does not
cross the blood-brain barrier. Limited data which indicate that doxorubicin crosses
the human placenta. Limited data indicate that it is distributed into milk, achieving
concentrations that often exceed those in plasma Doxorubicinol (the major
metabolite) also distributes into milk.
Metabolism Metabolized in the liver and other tissues by an aldo-keto reductase enzyme, yielding
doxorubicinol (the major metaboli te) 20% of the total drug in plasma is converted
to metabolites within 5 minutes after a dose, 70% in 30 minutes, 75% in 4 hours, and
90% in 24 hours.
Excretion Excreted predominantly in bile. 10- 20% is excreted in faeces in 24 hours, and 40-
50% is excreted in bile or faeces within 7 days. 4 to 5% is excreted in urine after 5
days, principally as unchanged doxorubicin.
Plasma concentrations decline in a triphasic manner:
First phase: rapid metabolism due to first-pass effect through the liver. Plasma half-
life of 0.6 hours for doxorubicin and 3.3 hours for the metabolites. Followed by
prolonged plasma concentrations, probably resulting from tissue binding.
Second phase: plasma half-life of doxorubicin is 16.7 hours, and that of its
metabolites is 31.7 hours. Plasma protein binding is approximately 50%.
Doxorubicin Hydrochloride. Adriamycin 149

INDICATIONS [4]
 Breast cancer

Adjuvant chemotherapy to surgery, or in metastatic disease.

 Advanced ovarian cancer

When a first-line platinum-based chemotherapy regimen has failed.

 Progressive multiple myeloma (in combination with Bortezomib)

In patients who have received at least one prior therapy, and who have already undergone
or cannot have bone marrow transplant.

 AIDS-related Kaposi's sarcoma

In patients with low CD4 counts (<200 CD4 lymphocytes/mm3) and extensive muco-
cutaneous or visceral disease.

 Acute lymphoblastic leukaemia


 Acute myeloblastic leukaemia
 Hodgkin‘s lymphoma
 Non-Hodgkin‘s lymphoma
 Peadiatric malignancies
 Metastatic Wilms' tumor, metastatic neuroblastoma
 Metastatic Sarcomas
 Soft tissue and bone
 Metastatic transitional cell bladder carcinoma
 Metastatic thyroid carcinoma
 Metastatic gastric carcinoma
 Metastatic bronchogenic carcinoma.

PREPARATIONS AND ADMINISTRATION [4, 5]


Doxorubicin is available as both conventional and liposomal formulations.

1. Doxorubicin (conventional):
 Injection, doxorubicin hydrochloride 2 mg/mL
 administered iv and intravesically.
 can be administered iv as a bolus within minutes, as a short infusion for up to an
hour, or as continuous infusion for up to 96 hours.
150 Z. Anwar

 given via the tubing of a freely running iv infusion of sodium chloride 0.9% or
dextrose 5% within 2 to 15 minutes.

2. Pegylated Liposomal Formulations:

Drug is encapsulated in liposomes with surface-bound methoxypolyethylene glycol


(MPEG). This protects liposomes from detection by the mononuclear phagocyte system,
which increases blood circulation time.

3. CAELYX
 1ml contains 2 mg doxorubicin.
 Administered ONLY as an iv infusion. Do not administer Caelyx as a bolus
injection or undiluted solution. May be given through a peripheral vein.
 For doses <90 mg: dilute in 250 ml 5% glucose solution for infusion.
 For doses ≥90 mg: dilute in 500 ml 5% glucose solution for infusion.

4. MYOCET 50mg powder


 Corresponds to 50 mg Doxorubicin hydrochloride (this preparation reduces the
distribution to heart and gastrointestinal mucosa compared with conventional
doxorubicin).
 Myocet, in combination with cyclophosphamide, is indicated for the first line
treatment of metastatic breast - cancer in adult women.
 Myocet must be reconstituted and diluted prior to administration - A final
concentration of between 0.4 mg/ml to 1.2 mg/ml is required.
 Administered by iv infusion over a period of 1 hour.

DOSAGES [4, 5]
Doxorubicin

Monotherapy:

 60 - 75 mg/m2 body surface area every three weeks.

Combination regimen (e.g., with cyclophosphamide/another anthracycline):

 Reduced to 30-60 mg/m2 every 3 – 4 weeks.

In patients who cannot receive the full dose (e.g., immunosuppression, old age), an
alternative dosage is 15-20 mg/m² body surface per week.
Intra-vesical instillation (for treatment of superficial bladder carcinoma or in prophylaxis
of tumour recurrence after resection):
Doxorubicin Hydrochloride. Adriamycin 151

 30-50 mg in 25-50 ml of sodium chloride (0.9%) solution


 optimal concentration is 1 mg/ml.
 should be retained intravesically for 1 to 2 hours. The patient should be turned 90°
every 15 minutes.
 patient should not drink fluids for 12 hours prior to treatment to avoid dilution with
urine.
 instillation may be repeated after 1 week to 1 month, dependent on whether the
treatment is therapeutic or prophylactic.

Caelyx

Breast Cancer/Ovarian Cancer


50 mg/m² intravenously once every 4 weeks.

Multiple Myeloma
30 mg/m² on day 4 of the bortezomib - 3 week regimen as a 1 hour infusion administered
immediately after the bortezomib infusion. The bortezomib regimen consists of 1.3 mg/m² on
days 1, 4, 8, and 11 (every 3 weeks).

AIDS-Related Kaposi’s Sarcoma


20 mg/m² every two-to-three weeks (at least two-to-three months is recommended to
achieve a therapeutic response).

Myocet

Metastatic Breast Cancer (First Line Treatment)


When administered in combination with cyclophosphamide (600 mg/m²) the initial
recommended dose is 60-75 mg/m² every three weeks.

For All Patients

For early symptoms or signs of infusion reaction, immediately discontinue the infusion,
give appropriate pre-medications (antihistamine and/or short acting corticosteroid), and restart
at a slower rate.

SPECIAL INFORMATION AND CAUTIONS [4, 5, 6]


All patients should undergo:

1. Frequent ECG monitoring (reduction of the QRS complex could indicate cardiac
toxicity. If this occurs, endomyocardial biopsy, must be considered.)
152 Z. Anwar

2. Echocardiography - evaluation of left ventricular function is mandatory.

Cardiac Impairment: Discontinue in patients who develop signs or symptoms of


cardiomyopathy.
Patients with impaired hepatic function: reduce dosage (refer to dosage adjustments)

Renal Impairment

As doxorubicin is metabolised by the liver and excreted in the bile, dose modification
should not be required (in the range of creatinine clearance 30-156 ml/min).

Hepatic Impairment

AIDS-related KS patients with splenectomy: no experience in patients who have had


splenectomy, therefore usage not recommended.

Pediatric Patients

Not recommended in patients below 18 years of age.

Elderly

No significant alterations in pharmacokinetics between age 21-75 years.

Pregnancy

Suspected to cause serious birth defects when administered during pregnancy.

Women of Child-Bearing Potential

Must be advised to avoid pregnancy while they or their male partner are receiving
doxorubicin, and for six months following discontinuation.

Breast-Feeding

It is not known whether doxorubicin is excreted in human milk. There is potential for
serious adverse reactions in nursing infants, therefore mothers must discontinue nursing prior
to beginning treatment.
Doxorubicin Hydrochloride. Adriamycin 153

Fertility

The effect on human fertility has not been evaluated.

TOXICITIES [5, 6]
Organic disorders Very common Common Uncommon Rare
≥1/10 ≥1/100 and <1/10 ≥1/1000 and ≥1/10,000 and
<1/100 <1/1000
Hair and skin Palmoplantar Dry skin, discolouration, Erythema
disorders erythema, alopecia, vesiculo-bullous eruption, multiforme,
rash dermatitis, nail disorder, Stevens Johnson
pruritus, maculopapular syndrome and
rash, sweating, acne toxic epidermal
necrolysis
Cardiovascular Ventricular arrhythmia, Venous
disorders vasodilatation, chest pain, thromboembolism,
oedema thrombophlebitis,
and pulmonary
embolism
Neurological Peripheral sensory Anxiety, depression, Confusion
disorders neuropathy, vertigo, insomnia, somnolence,
neuralgia, headache dizziness, hypertonia
Eye disorders Lacrimation, blurred vision,
epistaxis, malaise
Gastrointestinal Nausea, vomiting, Oesophagitis, gastritis,
disorders anorexia, stomatitis, dysphagia, weight loss, dry
mucositis, mouth, flatulence, gingivitis,
constipation, taste perversion
diarrhoea
Investigations Leukopaenia,
neutropaenia,
anaemia,
thrombocytopaenia
Gynae disorders Vaginitis, breast pain
Respiratory and Dyspnoea, cough,
thoracic disorders pharyngitis
Musculoskeletal Leg cramps, myalgia, back
disorders pain, bone pain
Infections and Pneumonia, oral candidiasis,
infestations folliculitis, conjunctivitis,
fungal infection, cold sores
(non-herpetic), upper
respiratory tract infection,
herpes zoster, urinary tract
infection
Neoplastic Secondary oral
disorders neoplasms
General disorders Fatigue Fever, decreased
appetite
154 Z. Anwar

DOSE MODIFICATIONS [4, 5]


Palmo-Plantar Skin Changes
Week after prior Caelyx dose
Toxicity grade at Week 4 Week 5 Week 6
current assessment
Grade 1 Redose unless As per week 4 Decrease dose by
patient has experienced a 25%; return to 4
previous grade 3 or 4 skin week interval
toxicity, in which case wait an
additional week
Grade 2 Wait an additional week Wait an additional week Decrease dose by
25%; return to 4
week interval
Grade 3 Wait an additional week Wait an additional week Withdraw patient
Grade 4 Wait an additional week Wait an additional week Withdraw patient

STOMATITIS
Week after prior Caelyx dose
Toxicity grade at Week 4 Week 5 Week 6
current assessment
Grade 1 Redose unless As per week 4 Decrease dose by 25%;
patient has experienced a return to 4 week interval or
previous grade 3 or 4 withdraw patient as per
stomatitis in which case physician's assessment
wait an additional week
Grade 2 Wait an additional week Wait an additional Decrease dose by 25%;
week return to 4 week interval or
withdraw patient per
physician's assessment
Grade 3 Wait an additional week Wait an additional Withdraw patient
week
Grade 4 Wait an additional week Wait an additional Withdraw patient
week

HAEMATOLOGICAL TOXICITY
GRADE Neutrophil Platelets Modification
count
Grade 1 1.5 – 1.9 75 – 150 Resume treatment with no dose reduction.
Grade 2 1.0 – 1.4 50 – 74 Wait until Neuts ≥1.5 and platelets ≥75 - redose with no
dose reduction.
Grade 3 0.5 – 0.9 25 – 49 As above
Grade 4 <0.5 <24 Wait until Neuts ≥1.5 and platelets ≥75; decrease dose by
25% or continue full dose with growth factor support.
Doxorubicin Hydrochloride. Adriamycin 155

Impaired Cardiac Function

To avoid cardiomyopathy, the cumulative lifetime dose of Doxorubicin (and other


anthracyclines) should not exceed 450-550mg/m2.
Patient with heart disease who are:

1. Receiving mediastinal and/or heart irradiation


2. Have hypertension since >5 years
3. Prior coronary, valvular or myocardial heart damage
4. Age over 70 years

A maximum total dose of 400 mg/m2 body surface area should not be exceeded, and
cardiac function of these patients should be monitored.

Impaired Hepatic Function

Dose adjustments according to bilurubin level:

Serum Bilirubin Recommended Dose


20-50 micro mol/L ½ normal dose
>50 micro mol/L ¼ normal dose

Doxorubicin can be administered to patients with liver metastases with concurrent


elevation of bilirubin and liver enzymes up to 4 x the upper limit of the normal range.

Impaired Renal Function

In patients with renal insufficiency (GFR <10 ml/min), only 75% of the planned dose
should be given.

INTERACTIONS [7]
Major Interactions:
Ciclosporin Increased risk of neurotoxicity when doxorubicin given with ciclosporin.
Clozapine Avoid use of cytotoxics with Clozapine (increased risk of agranulocytosis
Vaccines Avoid use of doxorubicin with live vaccines

Milder Interactions:
Cimetidine Reduces plasma concentration of doxorubicin.
Digoxin Doxorubicin possibly reduces absorption of digoxin tablets
Sorafenib Increase plasma concentration of doxorubicin
Verapamil
Stavudine Doxorubicin possibly inhibits effects of stavudine
156 Z. Anwar

Caution must be exercised when giving any other cytotoxic agents, especially myelotoxic
agents, at the same time.
In patients with AIDS, Doxorubicin may:

 exacerbate cyclophosphamide-induced haemorrhagic cystitis


 enhance the hepatotoxicity of 6-mercaptopurine

CONCLUSION
Doxorubicin is an antineoplastic agent which belongs to the family of anthracyclines. It
was isolated from a pigment of Streptomyces Peucetius (bacterium species), and introduced
in 1969 for cancer treatment. Doxorubicin has a very wide anti-tumour spectrum, compared
with other anticancer drugs. The most relevant side-effects are dose-limiting such as
hematologic and cardiac toxicities. The latter is dose-dependent and limits its long-term use
which may impact on results [1, 2].
There are several factors that increase the risk such as previous mediastinal radiation
therapy or left ventricular dysfunction and advanced age. Adriamycin-induced
cardiomyopathy may be prevented by limiting the total dose to 400 to 450 mg/m2 following
mediastinal radiation and 500 to 550 mg/m2 for patients without other significant risk factors.
Liposome-based drug delivery systems are able to modify the pharmacokinetics and
pharmacodynamics of cytostatic agents, enabling us to increase the concentration of the drug
into the neoplastic tissue and reduce the exposure of normal tissue to the agent. Liposome
encapsulation is one of the strategies designed to minimize this side effect. There are several
liposome-encapsulated doxorubicin formulations with different pharmacological
characteristics. The most commonly used are liposomal doxorubicin (Myocet) and pegylated
liposomal doxorubicin (Caelyx) [8].
An advantage with these products is that they have proven to be effective and safe when
combined with trastuzumab both in advanced and early breast cancer.

REFERENCES
[1] http://www.agrojournal.org – introduction to doxorubicin. 2014.
[2] http://en.wikipedia.org – intro to doxorubicin, mechanism of action. 3/2015.
[3] http://www.rxmed.com – pharmacokinetics. No date stated.
[4] http://www.drugs.com – indications, dosage and administration, adjustments. 11/2014.
[5] http://www.medicines.org.uk – doxorubicin preparation/dosages/adjustments/toxicity.
19/5/2006.
[6] http://www.macmillan.org.uk/- cancer treatment/chemotherapy. 1/1/14.
[7] www.bnf.org – interactions. 2015.
[8] Lao J, Madani J, Puértolas T, Álvarez M, Hernández A, Pazo-Cid R, Artal A, Antón-
Torres A. Liposomal Doxorubicin in the Treatment of Breast Cancer Patients: A
Review. J Drug Delivery. 2013. ID 456409.
In: The Easy Book of Cancer Pharmacology ISBN: 978-1-63485-038-4
Editor: Esther Una Cidon © 2016 Nova Science Publishers, Inc.

Chapter 18

ENZALUTAMIDE. XTANDI®. MVD3100

J. Ching
Clinical Oncology Department, Poole Hospital NHS Foundation Trust, Poole, UK

ABSTRACT
Enzalutamide is an oral anti-androgen which is currently licensed to be used in
metastatic castration resistant prostate carcinoma. It is more potent when compared to
bicalutamide and do not exhibit any partial agonist activity. Apart from being an
androgen receptor inhibitor, enzalutamide does target further downstream signaling
pathway. Based on the AFFIRM and PREVAIL study, enzalutamide is currently licensed
to be used in patients with metastatic castration resistant prostate carcinoma who
progressed after docetaxel chemotherapy and chemotherapy-naive groups. Enzalutamide
is relatively easy to tolerate minimal side effects. The most common side effects reported
are vascular disorder and fatigue. Rarer side effects include neuropsychiatric adverse
events for example, seizures, and memory impairments. Currently, enzalutamide is not
licensed to be used sequentially with abiraterone acetate outside of clinical trials.

Keywords: enzalutamide, anti-androgens, castration resistant prostate carcinoma

INTRODUCTION
Androgen deprivation therapy is the mainstay of treatment for advanced prostate cancer.
It is almost inevitable that as time goes by most advanced prostate cancer will be refractory to
maximal androgen blockade (castrate-resistant prostate cancer). The TAX 327 trial was
published in 2004, and this study shows a survival advantage with the use of three-weekly
docetaxel chemotherapy in a cohort of patient with castration-resistant prostate cancer [1].
However, the response rate is relatively modest with a median survival of approximately 19
months. As a consequent, there was a push for more development of novel targeted therapy
which is better tolerated and enzalutamide is one of them.


Email: HengJeng.Ching@poole.nhs.uk.
158 J. Ching

CLINICAL PHARMACOLOGY
Drug Classification

Anti-androgen

Mechanism of Action [1]

Enzalutamide has greater (approximately 5-8 folds) binding affinity with androgen receptor
(AR) when compared to bicalutamide. In comparison to bicalutamide, enzalutamide do not exhibit
any partial agonist activity with AR. Furthermore, by inhibiting the AR, enzalutamide blocks
activational changes induced by AR-testosterone binding. In addition to that, enzalutamide also
blocks AR-testosterone nuclear transcription and DNA transcription.
Enzalutamide is also found to decrease the growth of prostate cancer cells and induce
apoptosis.

Pharmacokinetics

Absorption Oral absorption is rapid and estimated to be 84%


Food does not affect absorption but peak plasma concentration of
enzalutamide was found to be 30% higher in fasted state
Distribution The mean apparent volume of distribution is 110L (extensive extravascular
distribution)
In preclinical animal model testing, both enzalutamide and N-desmethyl
enzalutamide (M2, active metabolite) was found to cross the blood brain
barrier
Enzalutamide is bound to primarily albumin (97-98%)
Active metabolite, M2 is also bound to plasma protein (95%)
Metabolism Enzalutamide is extensively metabolised by CYP2C8 (primarily) and
CYP3A4/5 (smaller proportion)
2 main metabolites (1) N-desmethyl enzalutamide (M2, active) and (2) a
carboxylic acid derivatives (M1, inactive)
Excretion Enzalutamide is predominately excreted with the renal system
71% is excreted via the urinary system as M1 (trace amounts of
enzalutamide and M2 is also found)
14% is found in the faeces
Terminal half-life of enzalutamide is 5.8 days
Adapted from standard references [3, 4].

Mechanism of Resistance

Like most cancer therapies, drug resistance remains an emerging issue. One of the
mechanisms described is an alteration of the gene arrangement of the AR caused by gene
Enzalutamide. Xtandi®. MVD3100 159

splicing. This results in a constitutionally active, truncated AR without any ligand binding
domain [5].
A study found that treatment with enzalutamide caused an increased in testosterone as
well as dihydrotestosterone (in both plasma and bone marrow) leading to drug resistance. It
was suggested that this may be due to an overexpression of CY17 and high levels of autocrine
and paracrine androgen synthesis [6].

Indications [7, 8]

Enzalutamide is currently indicated in metastatic castration resistance prostate carcinoma


after progression on or after docetaxel and in those patients who have not had docetaxel
chemotherapy and chemotherapy is still not indicated.

Dosages [3]

The recommended dose for enzalutamide is 160mg (four tablets of 40mg) once a day
until disease progression. Enzalutamide should be continued alongside with medical
castration with LHRH analogue unless patient is surgically castrated.

Methods of Preparation/Administration [4]

Enzalutamide is an oral medication that is taken whole with or without food.


Enzalutamide is supplied as a 40mg liquid filled capsules and sorbitol is found in the
capsules.

Special Information and Cautions [1, 3]

Contraindications
-Hypersensitivity to the drug or to the excipients listed below:
Capsule content
Macrogol-8 glycerides caprylocapryl
Butylhydroxyanisole (E320)
Butylhydroxytoluene (E321)
Gelatin
Capsule shell
Sorbitan sorbitol solution
glycerol
Titanium dioxide (E171)
Purified water
Black iron oxide (E172)
Printing ink
Polyvinyl acetate phthalate
160 J. Ching

Elderly
Dose adjustment is not necessary.

Pediatric
Not indicated in this population.

Renal Impairment
Dose adjustment is not needed in mild or moderate renal impairment. Caution if severe
renal impairment.

Hepatic Impairment
Dose adjustment is not needed in hepatic impairment, though a longer half-life has been
observed in severe hepatic impairment.

Immunisations
Live vaccines should not be applied while taking the treatment or for at least 6 months
afterwards. Other vaccines can be administered, though may not give as much protection as
usual. In any case, it is safe to be in contact with other people who have had live vaccines as
injections. There can be problems with oral vaccines. Any contacts with someone who has
had oral polio, cholera or typhoid vaccination recently, should be avoided.

Pregnancy
Recommended to use effective contraception methods while on the treatment and for 3
months afterwards.

Breast-Feeding
It is not indicated in women.

Warnings

Seizures
In the AFFIRM study, seizure were reported in 5 out of 800 (0.6%) patients receiving
enzalutamide treatment. In the PREVAIL study, one patient in both enzalutamide and placebo
arm reported to have experienced seizure [7, 8].
It is postulated that enzalutamide lowers the seizure threshold by inhibiting the γ-
aminobutyric acid–gated chloride channel. It is noted that these study excluded patients that
has underlying epilepsy [9].

Hypertension
Increased in systolic and diastolic blood pressure is observed in approximately 7% of
patients. However, enzalutamide is rarely discontinued or required dose modification. It is
noted that majority of patients that develops hypertension whilst on enzalutamide would
Enzalutamide. Xtandi®. MVD3100 161

require initiation of anti-hypertensive or increment of their current anti-hypertensive


medication [4].

Prolonged QTc
Enzalutamide is known to prolonged QTc interval. Therefore, extra caution is needed
with patient received concurrent medication that prolong QTc interval. It is recommended to
monitor ECG as well as serum electrolytes in at risk patients.

Toxicities [10]

System Organ Very Common Common Uncommon Rare


Class ≥1/10 ≥1/1000 ≥1/1,000 (≥1/10.000
to <1/10 to <1/1000 a < 1/1.000)
Cardiovascular Hypertension

Blood and Leucopenia,


lymphatic neutropenia
disorders
Endocrine Gynaecomastia
disorders
Nervous System Headache Anxiety Visual
disorders hallucinations
cognitive
disorders, seizure
Gastrointestinal Emetogenic
disorders potential
Hepatobiliary Deranged liver
disorders function test

Skin disorders Dry skin/pruritus


General disorders Fatigue, Peripheral oedema
hot flushes
Musculoskeletal Muscle aches,
disorders arthralgia,
fractures,
falls
Unknown frequency
Posterior reversible encephalopathy syndrome
QT interval prolongation
Nausea
Adapted from standard reference [10].

DOSE MODIFICATIONS
It is advised to reduce the dose of enzalutamide if a drug that inhibits CYP2C8 is
administered concurrently.
No dose adjustment required in mild to moderate renal impairment (CrCl >30ml/min).
There is no data regarding severe renal impairment.
162 J. Ching

In addition, there is no dose adjustment required in mild to moderate liver impairment


and no data is available for severe liver impairment.
Given that enzalutamide is highly bound to plasma protein with extensive volume of
distribution, hemodialysis or peritoneal dialysis is unlikely to have a significant effect on
plasma levels.

INTERACTIONS [4]
Enzalutamide is a strong enzyme inducer of CYP3A4 and a moderate inducer of
CYP2C9 and CYP2C19 [4]. Therefore, co-administering drugs that are metabolized by these
enzymes would result in a lower concentration of the substrate.
Midazolam - co-administration with enzalutamide would results in 86% decrease in AUC
of midazolam. Therefore, concurrent use is not recommended.
Omeprazole - co-administration with enzalutamide would results in 70% decrease in
AUC of omeprazole. Concurrent use with enzalutamide is therefore not advisable.
Warfarin - concurrent use with enzalutamide would cause 56% reduction in warfarin‘s
AUC. It is advised to monitor INR closely and titrate the warfarin dose according to the
desired therapeutic INR.

Other groups of medications with potential interactions are as follow:


analgesia - fentanyl, tramadol
antibiotics - clarithromycin, doxycycline
anticancer - cabazitaxel
anticoagulants - acenocoumarol
antiepileptics - carbamazepine, phenytoin, sodium valproate
antipsychotics -haloperidol
betablockers- bisoprolol, propanolol
calcium channel blocks - diltiazem, felopine, nicardipine, verapamil
cardiac glycosides - digoxin
corticosteroids - dexamethasone, prednisolone
hypnotics - diazepam
statins - atorvastatin, simvastatin
thyroid replacement agents - levothyroxine

The potential interaction may not be apparent until a month after starting enzalutamide.
The time needed to achieve steady-state plasma concentration following commencement of
enzalutamide. It is noted that the effect on the enzymes may persist for approximately a
month after cessation of enzalutamide therapy. This is because of the long half-life of
enzalutamide.
Enzalutamide. Xtandi®. MVD3100 163

CONCLUSION
Enzalutamide is potent oral antiandrogen which has excellent safety profile and it is very
well tolerated. Unlike docetaxel chemotherapy, enzalutamide is much easier to tolerate.
It does have anti-tumour activity in both chemotherapy-naive patients as well as patients
that have received prior chemotherapy as shown in both PREVAIL and AFFIRM study. In
addition to that, enzalutamide does not have the ill effects of mineralcorcticoid excess which
is caused by abiraterone acetate. Therefore no concurrent administration of corticosteroid is
required, reducing the pill burden. Moreover, enzalutamide rarely caused deranged liver
function test unlike abiraterone acetate. Therefore, patients receiving enzalutamide may not
need to have frequent blood test whilst on treatment.

REFERENCES
[1] Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisolone or mitoxantrone
plus prednisolone for advanced prostate cancer. The New England Journal of Medicine,
2004; 351:1502-1512.
[2] Hoffman-Censits J and Kelly WK. Enzalutamide: A novel antiandrogen for patients
with castrate-resistant prostate cancer. Clinical Cancer Research, 2013;19:1335-1339.
[3] BC Cancer Agency Cancer Drug Manual. Enzalutamide. http://www.bccancer.
bc.ca/drug-database-site/Drug%20Index/Enzalutamide_monograph_1June2015.pdf
(accessed 1 June 2015).
[4] Astellas Pharma Canada Inc. Xtandi® product monograph. http://www.
cmsastellas.ca/uploads/pdf/Xtandi_PM_EN-Approved_1.pdf (accessed 1 June 2015).
[5] Li Y, Chan SC, Brand LJ, et al. Androgen receptor splice variants mediate
enzalutamide resistance in castration-resistant prostate cancer cell lines. Cancer
Research 2012;73:483-489.
[6] Efstathiou E, Titus M, Wen S, et al. Molecular characterization of enzalutamide-treated
bone metastatic castration-resistant prostate cancer. European Urology, 2015;67:53-60.
[7] Scher HI, Fizazi K, Saad F, et. al. Increased survival with enzalutamide in prostate
cancer after chemotherapy. The New England Journal of Medicine, 2012;367:1187-
1197.
[8] Beer TM, Armstrong AJ, Rathkopf DE, et. al. Enzalutamide in metastatic prostate
cancer before chemotherapy. The New England Journal of Medicine, 2014;371:424-
433.
[9] Treiman DM. GABAergic mechanisms in epilepsy. Epilpesia. 2001;42:8-21.
[10] Electronic Medicine Compendium. Xtandi® 40mg soft capsules. https://www.
medicines.org.uk/emc/medicine/27912 (accessed 1 June 2015).
In: The Easy Book of Cancer Pharmacology ISBN: 978-1-63485-038-4
Editor: Esther Una Cidon © 2016 Nova Science Publishers, Inc.

Chapter 19

ERLOTINIB, TARCEVA®

S. Adeleke
Clinical Research Fellow, Clinical Research Facility, University College Hospital,
London, UK

ABSTRACT
Erlotinib is an oral epidermal growth factor receptor (EGFR) tyrosine kinase
inhibitor (TKI), which shows improvements in survival in patients with advanced non-
small cell lung cancer (NSCLC) who have previously received one or more prior
chemotherapy regimens. Depending on the region of the world and the accredited
indicated use by different drug agencies, it could be used either as 1st line or 2nd line
treatment for patients with NSCLC [1]. Erlotinib is recommended as an option for the
first-line treatment of patients with locally advanced or metastatic NSCLC if they test
positive for the EGFR-TK mutation.

Keywords: erlotinib, TKI, non-small cell lung cancer

INTRODUCTION
Erlotinib is an oral EGFR-TKI, which shows improvements in survival in patients with
advanced NSCLC who have previously received one or more prior chemotherapy regimens.
Erlotinib is generally well tolerated, with most adverse events being of mild to moderate
severity. Erlotinib is recommended, within its licensed indication, as an alternative to
Docetaxel as a second-line treatment option for patients with NSCLC only on the basis that it
is provided by the manufacturer at an overall treatment cost (including administration,
adverse events and monitoring costs) equal to that of docetaxel [2].


Sola Adeleke, e-mail: sola_adeleke2003@yahoo.com.
166 S. Adeleke

CLINICAL PHARMACOLOGY
Drug Classification

Antineoplastic, reversible EGFR-TKI [3]. TKI inhibition possibly blocks angiogenesis


and cellular proliferation.

Mechanism of Action

Many cancers such as NSCLC and pancreatic adenocarcinomas express EGFR on their
cell surfaces and some develop mutation in these receptors which favour cell proliferation and
survival. They achieve this by altering the ATP binding and downstream phosphorylation and
activation of pathways which eventually send signals to the nucleus for increased cell
proliferation, enhancing oncogenesis and evading tumour suppression and intrinsic anti-
apoptotic pathway [4].
Erlotinib binds tightly to the ATP binding site of the intra-cytoplasmic portion of the
EGFR thus inhibiting the other important downstream pathways. This happens in cells with
mutation of their EGFR i.e., exon 19 deletions or exon 21 L858R mutations [4].
Also of note but not necessarily significant in this context is that Erlotinib has been found
to strongly inhibit Jak2617F receptors which has been implicated in various
myeloproliferative disorders such as idiopathic myelofibrosis and Polycythemia rubra vera
[5].

Pharmacokinetics

Absorption Erlotinib is well absorbed in the stomach following oral administration and
absorption may be further accentuated when given with food.
It is usually advisable to give about 1 hour before food or 2 hours afterwards.
Its bioavalability is 60% but increases to almost a 100% with a full stomach [1].
It has a peak plasma level of about 4 hours following dosing.
Distribution It has got good tissue distribution and also sufficient tumour cell distribution and
penetration.
Over 90% bound to protein; albumin and alpha 1 acid glycoprotein [1].
Metabolism Erlotinib is metabolised in the liver primarily by the CYP3A4 and CYP1A2 and
1B1 in tumour tissue [1].
Excretion Its metabolite is mostly excreted in faeces and some excreted in the urine.
Its median half-life is about 36 hours and steady state plasma concentration
following continued daily use is about 7-8 days
Clearance: 24% higher in smokers. Excretion: Faeces 83%; urine 8% [1].
Erlotinib, Tarceva® 167

Mechanism of Resistance

Some cancer cells have been found to initiate mutation at the ATP binding pocket by
replacing threonine protein residue with a non-polar methionine residue escaping the
inhibitory mechanism of the EFGR inhibitor pathway [6]. Suppression of the activity of the
tumour suppressor gene PTEN and increasing the activitity of anti-apoptotic pathway
mediated by P13K [7, 8] and increased activity of mutated IGF receptors [9] are the other
mechanisms of resistance identified.

Indications

Erlotinib is indicated as 1st line treatment for metastatic NSCLC with EGFR mutations, or
NSCLC with locally advanced or metastatic disease that have failed 1st line of chemotherapy,
and as maintenance therapy in locally advanced or metastatic NSCLC with stable disease
after 4 cycles of platinum based chemotherapy [10].
Also, indicated in combination with Gemcitabine, in the treatment of metastatic
pancreatic cancer [10].

Dosages

It comes in 25 mg, 100 mg and 150 mg capsules. In NSCLC it is given as 150 mg once
daily usually until evidence of disease progression or until development of dose limiting
toxicity.
In pancreatic cancer it is recommended as 100 mg once daily [1].

Methods of Preparation/Administration

Oral preparation, usually administered 1 hr before food or 2 hours after food.

Special Information and Cautions [11]

Contraindications
Hypersensitivity to the active drug or to its excipients listed below:

Tablet core
 Lactose monohydrate
 Microcrystalline cellulose (E460)
 Sodium starch glycolate type A
 Sodium lauryl sulfate
 Magnesium stearate (E470 b)
168 S. Adeleke

The coating
 Hydroxypropyl cellulose (E463)
 Titanium dioxide (E171)
 Macrogol
 Hypromellose (E464)

Elderly
There are not specific studies in this population.

Pediatric
There are not specific studies in this population.

Renal Impairment
It is not excreted significantly in urine and pharmacokinetic studies did not show a
significant relationship between erlotinib and creatinine clearance. However, no data to
support use in advanced renal impairment but could be used depending on clinical
circumstances in patients with mild to moderate kidney disease [12].

Hepatic Impairment
There are no data suggesting a relationship between hepatic dysfunction and erlotinib
clearance but the increase in bilirubin was associated with a slower erlotinib clearance.
No data to support use in severe hepatic impairment but could be used depending on
clinical circumstances in patients with mild to moderate hepatic impairment [12].

Immunisations
Live vaccines should not be applied while taking the treatment or for at least 6 months
afterwards. Other vaccines can be administered, though may not give as much protection as
usual. In any case, it is safe to be in contact with other people who have had live vaccines as
injections. There can be problems with oral vaccines. Any contacts with someone who has
had oral polio, cholera or typhoid vaccination recently, should be avoided.

Pregnancy
Avoid pregnancy while taking the tablets and at least for two weeks after the last tablet.

Breast-Feeding
This should be avoided while taking the medication.

Warnings

Myocardial Infarction (MI)/Ischemia


The risk of MI is increased in patients with pancreatic cancer.
Erlotinib, Tarceva® 169

Interstitial Lung Disease (ILD)


It occurs in 1.1% of patients. Treatment should be stopped if new or progressive
unexplained pulmonary symptoms such as dyspnea, cough and fever. This is usually
exacerbated in individuals with underlying chronic obstructive pulmonary disease, smokers or
patients with multiple pulmonary metastases. If finally ILD is diagnosed, treatment should be
definitively stopped.

Gastrointestinal Perforations
Discontinue.

Renal Impairment
If severe renal impairment, erlotinib needs to be stopped.

Hepatotoxicity
It includes hepatic failure and hepatorenal syndrome. Withhold or discontinue the
treatment for severe or worsening liver tests.

Bullous and Exfoliative Skin Disorders


Discontinue.

Ocular Disorders
Discontinue if corneal perforation, ulceration or persistent severe keratitis.

Cerebrovascular Accident (CVA)


The risk of CVA is increased in patients with pancreatic cancer.

Microangiopathic Hemolytic Anemia (MAHA)


The risk of MAHA is increased in patients with pancreatic cancer.

Hemorrhage in Patients Taking Warfarin


Monitor INR in patients taking warfarin or other coumarin-derivative anticoagulants.

Note

Smoking has been known to reduce the efficacy of Erlotinib [10]. Patients are encouraged
to stop smoking before commencement of treatment. Or patients might need higher doses if
there is history of concurrent smoking.
170 S. Adeleke

Toxicities [11]

Organic system Very Common Common ≥1/1000 to Uncommon ≥1/1,000 Rare


disorders ≥1/10 <1/10 to <1/1000 (≥1/10.000 a
<1/1.000)
Renal disorders Renal impairment Nephritis, proteinuria
Respiratory, Epistaxis, severe
thoracic and interstitial pulmonary
mediastinal disease
disorders
Organic system Very Common Common ≥1/1000 to Uncommon ≥1/1,000 Rare
disorders ≥1/10 <1/10 to <1/1000 (≥1/10.000 a
<1/1.000)
Gastrointestinal Diarrhoea** Gastrointestinal Perforation Hepatic failure
disorders haemorrhages
Hepatobiliary Abnormal
disorders hepatic tests
Skin and Alopecia, dry skin, Mild Palmo-plantar
subcutaneous tissue paronychia, folliculitis, hyperpigmentation, erythrodysesthesia
disorders acneiform*, dermatitis, brittle and loose nails,
skin splits hirsutism, eyebrows
changes
Eye disorders Keratitis, conjuctivitis Eyelash changes,
ingrowth, thickening
Unknown frequency
Corneal perforation, ulceration
Uveitis
Steven Johnson‘s syndrome
Chest pain
*
One of the most common side effects associated with Erlotinib is the acneiform rash which is often
generalised and could sometimes be used as a marker of efficacy [12]. ** In combination with
Gemcitabine, toxicities such as rash and diarrhoea may be significantly increased, so are
hepatoxicity and immunosupression leading to higher risks of developing neutropenic sepsis [11].

Dose Modifications

If dose limiting toxicity develops, treatment might be discontinued until resolution of


symptoms and then appropriately reviewed for likely dose reduction in doses usually of 50
mg [11, 12] steps or outright termination of line of treatment if future risks potentially
outweighs benefits.

CONCLUSION
Treatment of advanced-stage NSCLC is rapidly evolving. Recently the combination
between antiangiogenic agents and EGFR TKIs is a novel approach that has shown some
improvements in progression free survival with bevacizumab and erlotinib. Unfortunately
overall survival has not been encouraging and further research is needed. Other studies
Erlotinib, Tarceva® 171

combining bevacizumab or ramucirumab with targeted therapies in the EGFR mutation-


positive patients are expected in the following years which could help tailor the therapeutic
approach for these populations [13].

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172 S. Adeleke

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Mechanism Involving the IGF1R Pathway. Cancer Research. 2012;73(2):834-843.
[23] Ayoola A, Barochia A, Belani K, Belani C. Primary and Acquired Resistance to
Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Non-small Cell Lung
Cancer: An Update. Cancer Investigation. 2012;30(5):433-446.
[24] Hanan E, Eigenbrot C, Bryan M, Burdick D, Chan B, Chen Y et al. Discovery of
Selective and Noncovalent Diaminopyrimidine-Based Inhibitors of Epidermal Growth
Factor Receptor Containing the T790M Resistance Mutation. Journal of Medicinal
Chemistry. 2014;57(23):10176-10191.
[25] Zugazagoitia J, Puente J, González-Larriba J, Manzano A, Sotelo M, Hernández S et al.
Erlotinib versus Pemetrexed for Pretreated Non-Squamous Non-Small Cell Lung
Cancer Patients in Clinical Practice. Oncology. 2013;84(5):255-264.
In: The Easy Book of Cancer Pharmacology ISBN: 978-1-63485-038-4
Editor: Esther Una Cidon © 2016 Nova Science Publishers, Inc.

Chapter 20

ETOPOSIDE: VP16: VEPESID: ETOPOPHOS

Z. Anwar
Oncology Department, Poole Hospital NHS Foundation Trust, Poole, UK

ABSTRACT
Etoposide is a cytotoxic anticancer drug first synthesized in 1966. The chemical
make-up is derived from podophyllotoxin, a toxin found in the North American May
apple. It has been used as an anticancer agent for longer than three decades, and it was
first approved by the US in 1963. It inhibits DNA topoisomerase II. The first clinical trial
of etoposide was reported in 1971, and etoposide entered routine use after 1981.
Etoposide is one of the most widely used cytotoxic drugs and has strong antitumor
activity in several tumours such as small-cell lung cancer, testicular cancer, lymphomas
and a variety of childhood malignancies.

Keywords: etoposide, VP16, podophyllotoxin

INTRODUCTION
Etoposide is a topoisomerase II inhibitor with activity against several types of tumours
such as small-cell lung cancer, testicular cancer, lymphomas, Kaposi‘s sarcoma and a variety
of childhood malignancies. It is a cell-cycle specific agent with activity in late S- and G2-
phases and it needs to be dephosphorylated to be active. Once it is active, it inhibits
topoisomerase II-DNA complex and prevents the unwinding of DNA. Its current therapeutic
use is limited by myelosuppression, mainly neutropenia.


Zunera Anwar, zuneraanwar@hotmail.com.
174 Z. Anwar

CLINICAL PHARMACOLOGY
Drug Classification [1]

Topoisomerase II inhibitor

Mechanism of Action [1, 3]

It acts primarily in the G2 and S phases of the cell cycle and forms a ternary complex
with DNA and the topoisomerase II enzyme (which aids in DNA unwinding). This prevents
re-ligation of the DNA strands, causing DNA strands to break.
Cancer cells rely on this enzyme more than healthy cells, since they divide more rapidly.
Etoposide causes errors in DNA synthesis and promotes apoptosis.

Pharmacokinetics [4]

Absorption  Following intravenous administration, etoposide phosphate is rapidly and completely


converted to etoposide in plasma.
Distribution  Has a distribution half-life of about 1.5 hours and an elimination half-life ranging from
4 to 11 hours.
 Does not accumulate in the plasma following daily administration of the correct dose.
 Enters the CSF poorly. Although it is detectable in CSF and intracerebral tumours, the
concentrations are lower than in extra-cerebral tumours and in plasma.
 Etoposide concentrations are higher in normal lung than in lung metastases, and are
similar in primary tumours and normal tissues of the myometrium.
 In vitro, etoposide is highly protein bound (97%) to human plasma proteins.
Metabolism  No evidence of a first-pass effect for Etoposide.
 The major metabolic pathway involves O-demethylation to etoposide catechol by
cytochrome P450 3A4 (CYP3A4).
Excretion  Excreted by both renal and non- renal processes, i.e., metabolism and biliary excretion.
 In adults, the total body clearance of Etoposide is correlated with creatinine clearance,
serum albumin concentration, and non-renal clearance.

Indications [3, 5]

It is indicated in adults (with other chemotherapeutic agents) for the management of:

 refractory non-seminomatous testicular tumours.


 first line testicular tumours.
 small cell lung cancer
 acute monoblastic leukaemia (AML M5) and acute myelomonoblastic leukaemia
(AML M4) when standard induction therapy has failed.
 Hodgkin's Disease - in combination with other chemotherapeutic agents as a part of
the BEACOPP, EVA and BEAM regimens.
Etoposide: VP16: Vepesid: Etopophos 175

Dosages [5]

 recommended dose is 60-120 mg/m2 intravenously (iv) per day for a total of 5 days.
 must not be repeated more often than every 10 to 20 days (as it causes
myelosuppression)
 for non-haematological indications, courses should not be repeated more often than
21 day intervals.

Usual dosage schedules:

1. 100 mg/m2 for 5 days OR


2. 120 mg/m2 every other day on days 1, 3, and 5.

Oral preparations dosage: recommended course of Vepesid capsules is 120-240 mg/m²


orally daily, for three to five consecutive days.

Methods of Administration/Preparation [5]

Preparations:

1. Etopophos 100mg Powder for Solution for Injection


2. Etoposide 20 mg/ml Concentrate for Solution for Infusion
3. Vepesid Soft Capsules 50 mg and 100 mg

Administration:

 Intravenous:
 Etoposide must be diluted with 5% glucose or 0.9% sodium chloride, to achieve
a final concentration of 0.2-0.4 mg/ml of etoposide (i.e., 1 ml or 2 ml concentrate
in 100 ml of diluent).
 Administered as an IV solution over a period of 30 minutes to 2 hours.

Special Information and Cautions [3, 5]

Contraindications
 Hypersensitivity to the drug or to the excipients.
 Severe hepatic impairment.
 Severe renal impairment (creatinine clearance <15 ml/min).
 Severe myelosuppression.
 Breast-feeding

Elderly
It is not needed to adjust the dosage.
176 Z. Anwar

Pediatric
Safety and efficacy not established in this population.

Renal Impairment
Dose should be adjusted based on creatinine clearance.
>50 ml/min to use 100%
15-50 ml/min to use 75%
<15ml/min it is contraindicated

Hepatic Impairment
Contraindicated if severe hepatic impairment. Dose reduction may be necessary.

Immunisations
Live vaccines should not be applied while taking the treatment or for at least 6 months
afterwards. Other vaccines can be administered, though may not give as much protection as
usual. In any case, it is safe to be in contact with other people who have had live vaccines as
injections. There can be problems with oral vaccines. Any contacts with someone who has
had oral polio, cholera or typhoid vaccination recently, should be avoided.

Pregnancy
Etoposide can cause fetal harm when administered to a pregnant woman. Both males and
female patients use effective contraception during treatment and up to 6 months after
treatment.

Breast-Feeding
It is not known whether these drugs are excreted in human milk, therefore breastfeeding
should generally be avoided.

Warnings

Myelosuppression
Dose-related and dose-limiting, with granulocyte nadirs occurring 7 to 14 days after drug
administration, and platelet nadirs occurring at 9 to 16 days.
Bone marrow recovery is usually complete by day 20, and no cumulative toxicity has
been reported. At the start of treatment and before each subsequent dose, the following should
be checked: platelet count, hemoglobin and total and differential count of leukocytes. Before
treatment is started, bacterial infections should be brought under control.

Anaphylaxis
Infusion should be terminated immediately, followed by the administration of adrenaline,
corticosteroids, antihistamines, or volume expanders.
Etoposide: VP16: Vepesid: Etopophos 177

Hypotension
The infusion should be given slowly, during 30 to 60 minutes, to avoid hypotension or
bronchospasm.

Skin Reactions
Use of gloves is recommended. If there is contact with skin or mucosa, immediately wash
thoroughly with soap and water.

Mutagenicity and Carcinogenicity


This should be taken into account when a long-term treatment is performed. Occurrence
of acute leukaemia has been reported rarely.

Liver and Renal Impairment


In patients with a lower serum albumin level, the risk of toxicity can be elevated. If the
patient is suffering from hepatic or renal dysfunction, these should regularly monitored due to
the risk of accumulation.

Fertility
Genetic counseling is recommended if the patient wants to have children after treatment.

Toxicities [5]

Organ system class Very common Common (≥1/100 Uncommon Rare (≥1/10,000 to
disorders (≥1/10) to <1/10) (≥1/1,000 to <1/1,000)
<1/100)
Haematology Myelosuppression Acute leukaemia
disorders
Cardiology Myocardial Hypotension
disorders infarction, following rapid
arryhthmia IV administration,
Hypertension
Immune system Anaphylactic type
disorders reactions
Metabolic disorders Hyper-uricaemia
Central Nervous Dizziness Peripheral Seizures, cortical
system disorders neuropathy blindness,
somnolence, fatigue
Eye disorders Transitory loss of
vision, optic neuritis
Respiratory disorders Pulmonary fibrosis,
interstitial
pneumonitis
Gastrointestinal Abdominal pain, Mucositis, diarrhoea Dysphagia,
disorders constipation, nausea dysgeusia
and vomiting, anorexia
Hepato-biliary Hepatotoxicity
disorders
Dermatology Alopecia, pigmentation Rash, 177rticarial, Stevens-johnson
disorders pruritus syndrome, radiation
recall dermatitis
Others Malaise Extravasation,
phlebitis
178 Z. Anwar

Dose Modifications [3, 5]

Etoposide Cycles Should Not Begin If:

1. The neutrophil count is less than 1.5 x 109/L.


2. The platelet count is less than 100 x 109/L, unless caused by malignant disease.

Doses Following the First Dose Should Be Adjusted if:

1. The neutrophil count is less than 0.5 x 109/L for more than 5 days, or if this is
associated with fever or infection.
2. The platelet count is less than 25 x 109/L.
3. Development of severe toxicity.
4. Creatinine clearance is less than 50 ml/min.

Patients with Impaired Renal Function:

Creatinine clearance (ml/min) Dose


>50 100% of the dose
15-50 75% of dose

Patients with Impaired Hepatic Function:

Bilirubin 25-50 umol/L or AST 60 to 180 units Administer 50% of the normal dose.
Bilirubin 51 to 85 umol/L or AST greater than 180 units Administer 25% of the normal dose.
Bilirubin greater than 85 umol/L Recommended not to use.

Interactions [6]

Major Interactions:

Coumarins (Warfarin) Etoposide enhances anti-coagulant effect of Coumarins.


Clozapine Avoid concomitant use of cytotoxics with Clozapine - increased
risk of agranulocytosis.

Milder Interactions:

Cyclosporin Plasma concentration of Etoposide increased by Cyclosporin -


therefore increased risk of toxicity
Fosphenytoin/Phenytoin/ Plasma concentration of Etoposide reduced by these agents.
Phenobarbital/Primidone
Etoposide: VP16: Vepesid: Etopophos 179

CONCLUSION
Etoposide is a topoisomerase II inhibitor with activity against several types of tumours. It
is a cell-cycle specific agent with activity in late S- and G2- phases and it needs to be
dephosphorylated to be active. Once it is active, it inhibits topoisomerase II-DNA complex
and prevents the unwinding of DNA. Its current therapeutic use is limited by
myelosuppression, mainly neutropenia. It should be used with caution in patients with
abnormal renal function and dose reduction is recommended in this setting.

REFERENCES
[1] www.wikipedia.org. Title, introduction and drug classification. 11/10/2014.
[2] http://etoposide.cancertreatment.net/. Introduction. 2015.
[3] http://www.drugs.com/Mechanism of action, Indications, Cautions, Dose modifyca-
tions. 2-4/2015.
[4] http://packageinserts.bms.com/pi/pi_etopophos.pdf. Pharmacokinetics. 9/2013.
[5] https://www.medicines.org.uk/emc/medicine/29330. Indications, Dosages, Administra-
tion, Cautions, Toxicities, 03/06/2014.
[6] www.bnf.org. Interactions. 2015.
In: The Easy Book of Cancer Pharmacology ISBN: 978-1-63485-038-4
Editor: Esther Una Cidon © 2016 Nova Science Publishers, Inc.

Chapter 21

EVEROLIMUS. AFINITOR®

Y. Inam
Oncology Department, Royal Bournemouth Hospital, Bournemouth, UK

ABSTRACT
Everolimus is an orally administered inhibitor of the mammalian target of rapamycin
(mTOR), a therapeutic target for metastatic renal cell carcinoma and with activity against
other tumour types such as breast cancer and pancreatic neuroendocrine tumours (PNET)
[1-3]. mTOR inhibition reverses trastuzumab resistance and overcomes endocrine
resistance in breast cancer cells. It also prolongs progression-free survival in advanced
PNET with carcinoid syndrome and in advanced renal carcinoma after progression on
other treatments [1-3].

Keywords: Everolimus, mTOR

INTRODUCTION
Everolimus is a mTOR inhibitor. These inhibitors have shown antitumor activity as they
disrupt various signalling pathways leading to impaired cellular growth, proliferation and
survival. Several studies have shown that mTOR inhibitors use in combination with hormonal
therapy has shown promising results in overcoming endocrine resistance in breast cancer
cells. mTOR inhibition reverses trastuzumab resistance via the hyperactivated
PIK/AKT/mTOR pathway due to PTEN loss, by sensitising PTEN-deficient tumours to
trastuzumab [1-3].
mTOR is also a therapeutic target for metastatic renal cell carcinoma and has shown
antitumour activity in patients with advanced PNET [1, 2].
Adverse events with everolimus were mostly mild to moderate in severity. Major
toxicities include stomatitis, non-infectious pneumonitis and hyperglycemia.


Yasir Inam, drinam3@gmail.com.
182 Y. Inam

CLINICAL PHARMACOLOGY
Drug Classification [4, 5]

It is a targeted therapy classified as mTOR kinase inhibitor.

Mechanism of Action [4, 5]

Everolimus is a mTOR kinase inhibitor (mammalian target of rapamycin, which is a


serine-threonine kinase, downstream of the PI3K/AKT pathway, which is dysregulated in
several human cancers).
It binds to FKBP-12 (intracellular protein) and it forms an inhibitory mTOR complex 1
(mTORC1) which inhibits mTOR kinase activity. It also reduces activity of S6 ribosomal
protein kinase (S6K1) and eukaryotic elongation factor 4E-binding protein (4E-BP1), inhibits
expression of hypoxia-inducible factor (eg, HIF-1) and reduces expression of vascular
endothelial growth factor (VEGF). The inhibition of mTOR reduces cell proliferation,
angiogenesis and glucose uptake.

Indications [4, 5]

Breast Cancer
In postmenopausal women with advanced hormone receptor-positive, HER2-negative
breast cancer in combination with exemestane after failure of letrozole or anastrozole.

Renal Cancer
Advanced renal cell cancer, after failure with sunitinib and sorafenib.

Pancreatic Neuroendocrine Tumours (PNET)


Progressive PNET not surgically resectable or metastatic.

Renal Angiomyolipoma
Noncancerous kidney tumors (renal angiomyolipomas) with tuberous sclerosis complex
(TSC) in patients not requiring immediate surgery.

Mechanism of Preparation/Administration [4, 5]

It is given as a tablet by mouth. Recommended to take it at the same time each day and it
may be taken with or without food. Swallow whole with a glass of water, do not chew or
crush tablets.
Everolimus. Afinitor® 183

Dosage [4, 5]

10 mg PO qDay consistently with or without food.

Pharmacokinetics [4, 5]

Absorption Quickly absorbed


Peak Plasma Time 1.3-1.8 hours
Steady state is reached within 7 days.
Distribution Protein bound 74%
Metabolism CYP3A4 substrate and PgP substrate and moderate inhibitor.
It is also a competitive inhibitor of CYP3A4 and mixed inhibitor of CYP2D6.
In human plasma there have been found six metabolites but the most important
action is performed by everolimus itself.
Elimination Half Life: 30 hours
Excretion: 80% faeces; 5% urine

Special Information and Cautions [4, 5]

Contraindications
-Hypersensitivity to everolimus or rapamycin (sirolimus) derivatives and its excipients
listed below:

Butylated hydroxytoluene (E321)


Magnesium stearate
Lactose monohydrate
Hypromellose
Crospovidone type A
Anhydrous lactose

Elderly
No dose adjustment.
Pediatric
Safety and efficacy not established.
Renal impairment
No dose adjustment is needed.
Hepatic impairment

Child-Pugh A 7.5 mg daily


Child-Pugh B 5 mg daily
Child-Pugh C Use only indicated if benefit outweights the risks and in these
cases only 2.5 mg daily
184 Y. Inam

Immunisations
Live vaccines should not be applied while taking the treatment or for at least 6 months
afterwards. Other vaccines can be administered, though may not give as much protection as
usual. In any case, it is safe to be in contact with other people who have had live vaccines as
injections. There can be problems with oral vaccines. Any contacts with someone who has
had oral polio, cholera or typhoid vaccination recently, should be avoided.

Pregnancy
Everolimus can cause fetal harm. Female patients of reproductive potential should be
recommended to use highly effective contraception while receiving everolimus and for up to
8 weeks after finishing the treatment.

Breast-Feeding
Unknown if it is excreted in human milk. No nursing is recommended while on the
treatment.

Warnings [4, 5]

Infections
While taking everolimus, the risk of infections increases. Signs and symptoms should be
monitored and a treatment should be started early.

Renal Failure
Several cases have been observed, some with fatal outcome. Monitor renal function.

Mouth Ulcers
Stomatitis and oral mucositis are common. Management includes mouthwashes (without
alcohol or peroxide) and topical treatments.

Non-Infectious Pneumonitis

Monitor for clinical symptoms or radiological changes; fatal cases have occurred.
Manage by dose reduction or discontinuation until symptoms resolve, and consider use of
corticosteroids.

Laboratory Alterations
Elevations of serum creatinine, blood glucose and lipids may occur.
Decreases in haemoglobin, neutrophils, and platelets may also occur.
Monitor all these parameters prior to treatment and periodically thereafter.
Everolimus. Afinitor® 185

Toxicity [4, 5]

Organic disorders Very common Common Uncommon Rare


≥1/10 ≥1/100 and <1/10 ≥1/1000 and ≥1/10,000 and
<1/100 <1/1000
Hair and skin Dry skin, itchiness, rash Wound healing
disorders alteration
Eye disorders Eyelids edema Conjunctivitis
Renal disorders Acute kidney
injury
Neurological Headaches Insomnia
disorders
Blood disorders Red cells
aplasia
General disorders Fatigue, pyrexia, Haemorrhage Hot flushes, non
peripheral oedema, cardiac chest
weight loss, menstrual pain
irregularities
Gastrointestinal Stomatitis, constipation, Ageusia
disorders diarrhoea, nausea,
anorexia, vomiting
Investigations Anemia, hyperglycemia, Hypertrigliceride-mia, Pancytopenia
lymphopenia, thrombocyto- penia,
hypercholestero-lemia neutropenia,
lymphopenia,
hypocalcemia,
hypokalemia
Cardiovascular Cardiac failure,
disorders thromboembolic
events
Respiratory and Cough, pneumonitis,
thoracic disorders dyspnea
Infections and Infections such as
infestations Herpes zoster,
opportunistic infections
and Hepatitis B
ENT disorders Epistaxis
Immunological Hypersensi- Angioedema
disorders tivity

Dose Modifications [4, 5]

Toxicity Grade 2 Grade 3 Grade 4


Stomatitis Stop until grade 1 or less Stop until grade 1 or less Stop treatment
and restart at same level. and restart at 5 mg
If recurrence stop again
until grade 1 or less and
restart at 5 mg
186 Y. Inam

(Continued)

Toxicity Grade 2 Grade 3 Grade 4


Non-infectious pneumonitis Stop until grade 1 or less Stop until grade 1 or less Stop treatment
and restart at 5 mg. If and restart at 5 mg. If
recurrence stop recurrence stop
Febrile neutropenia Not applicable Stop until grade 2 or less Stop treatment
without fever and restart at
5 mg
Neutropenia No dose adjustment Stop until grade 2 or less Stop treatment
and restart at same dose
Thrombocytopenia Stop until grade 1 or less Stop until grade 1 or less Stop until grade 1 or
and restart at same dose and restart at 5 mg less and restart at 5
mg
Metabolic events No dose adjustment Stop until grade 1 or less Stop treatment
and restart at 5 mg
Other toxicities If tolerable, to continue Stop until grade 1 or less Stop treatment
If intolerable to stop until and restart at 5 mg. If
grade 1 or less and then recurrence stop
restart at same dose
If recurrence to stop until
grade 1 or less and restart
at 5 mg

Dosage modifications may be required if toxicities grade 3, 4 or recurrent grade 2.


If a reduction is performed, it is generally recommended not to go below 5 mg (except in
those cases with liver insufficiency Child-Pugh C).

Interactions [4, 5]

Potent inhibitors of CYP3A4/PgP


Antifungal except fluconazole Not recommended
Clarithromycin
Antiretrovirals
Moderate inhibitors of CYP3A4/PgP
Erythromycin If used concomitantly it may be necessary to reduce
Fluconazole the dose of everolimus
Diltiazem
Verapamil
Grapefruit juice Not recommended
Potent and moderate inductors of CYP3A4/PgP
Rifampicin If used concomitantly it may be necessary to increase
Dexamethasone the dose of everolimus
Carbamazepine, fenitoin
Hypericum Perforatum Not recommended
Everolimus. Afinitor® 187

CONCLUSION
Everolimus is a mTOR inhibitor which have shown antitumor activity by leading to
impaired cellular growth, proliferation and survival. Several studies have shown that mTOR
inhibitors use in combination with hormonal therapy has shown promising results in
overcoming endocrine resistance in breast cancer cells and reverses trastuzumab resistance.
mTOR is also a therapeutic target for metastatic renal cell carcinoma and has shown
antitumour activity in patients with advanced PNET [1-3].
Adverse events with everolimus were mostly mild to moderate in severity. Major
toxicities include stomatitis, non-infectious pneumonitis and hyperglycemia.

REFERENCES
[1] Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, Grünwald V,
Thompson JA, Figlin RA, Hollaender N, Urbanowitz G, Berg WJ, Kay A, Lebwohl D,
Ravaud A; RECORD-1 Study Group. Efficacy of everolimus in advanced renal cell
carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet
2008;372 (9637):449-456.
[2] James C. Yao, Manisha H. Shah, Tetsuhide Ito, Catherine Lombard Bohas, Edward M.
Wolin, Eric Van Cutsem, Timothy J. Hobday, Takuji Okusaka, Jaume Capdevila,
Elisabeth G.E. de Vries, Paola Tomassetti, Marianne E. Pavel, Sakina Hoosen, Tomas
Haas, Jeremie Lincy, David Lebwohl, Kjell Öberg for the RAD001 in Advanced
Neuroendocrine Tumors, Third Trial (RADIANT-3) Study Group. Everolimus for
Advanced Pancreatic Neuroendocrine Tumors. N. Engl. J. Med. 2011; 364:514-523.
[3] Aapro M, Andre F, Blackwell K, Calvo E, Jahanzeb M, Papazisis K, Porta C, Pritchard
K, Ravaud A. Adverse event management in patients with advanced cancer receiving
oral everolimus: focus on breast cancer. Ann. Oncol. 2014;25(4):763-73.
[4] Affinitor, INN-Everolimus, Europe. http://www.ema.europa.eu/docs/es_ES/document_
library/EPAR_-_Product_Information/human/001038/WC500022814.pdf.
[5] Affinitor, everolimus. http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/
022334s016lbl.pdf.
In: The Easy Book of Cancer Pharmacology ISBN: 978-1-63485-038-4
Editor: Esther Una Cidon © 2016 Nova Science Publishers, Inc.

Chapter 22

GEFITINIB

S. Adeleke
Clinical Research Fellow, Clinical Research Facility, University College Hospital,
London, UK

ABSTRACT
Gefitinib specifically inhibits the tyrosine kinase (TK) activity of the epidermal
growth factor receptor (EGFR) type 1 by interfering with the adenosine triphosphate
(ATP) binding site. About 10% of patient with non-small cell lung cancer (NSCLC) in
the US and about 35% in East Asia have EGFR mutations [1]. Hence gefitinib and the
other EGFR inhibitor erlotinib are inevitably important in treatment of NSCLC, of the
adenocarcinoma variant with the above mutation.

Keywords: gefitinib, EGFR, non-small cell lung cancer

INTRODUCTION
Gefitinib is a small molecule that specifically inhibits the tyrosine kinase (TK) activity of
the epidermal growth factor receptor (EGFR) type 1 by interfering with the adenosine
triphosphate (ATP) binding site. About 10% of patient with non-small cell lung cancer
(NSCLC) in the US and about 35% in East Asia have EGFR mutations [1]. Hence gefitinib
and the other EGFR inhibitor erlotinib are inevitably important in treatment of NSCLC, of the
adenocarcinoma variant with the above mutation.


Sola Adeleke, E-mail: sola_adeleke2003@yahoo.com.
190 S. Adeleke

CLINICAL PHARMACOLOGY
Drug Classification

Antineoplastic, reversible EGFR-TKI [2]. TKI inhibition possibly blocks angiogenesis


and cellular proliferation.

Mechanism of Action

Gefitinib selectively compete for the ATP binding site of the cytoplasmic tail of TK
domain of the EGFR receptor [2]. This effectively blocks the autophosphorylation of this
enzyme domain and subsequently leads to down regulation of downstream pathways which
are erstwhile responsible for angiogenesis, metastasis and tumour invasion. It also
importantly blocks the anti-apoptotic downstream cascade of the Ras Oncogene.
These numerous cellular biochemical activities are responsible for the very effective
ability of Gefitinib to slowdown or inhibit the progression of EGFR positive cancers. On the
other hand, after some prolonged exposure to the drug, the cell could potentially circumvent
some of these pathways or amplify this receptor to become resistant to the drug [3].

Pharmacokinetics

Absorption Oral bioavailability, mean: 60%


Peak plasma concentration: 3-7 hr
Steady-state achieved: 10 days
No significant interaction with food intake noted.
The use of proton pump inhibitors or H2 receptor antagonists, have been found to
slowdown the absorption of Gefitinib.
Distribution Well distributed in the body with enhanced good tissue absorption and
penetration.
About 90% bound to protein particularly albumin and alpha 1 acid glycoprotein.
Metabolism Chiefly metabolised by CYP3A4 (a P450 iso-enyzyme) in the liver to O-
desmethyl Gefitinib which is a much less potent derivate of the parent drug.
Excretion 90% faeces
Less than 5% urine
The remainder in other body fluids or secretions.
Half-life is about 28hours.
There is incremental accumulation of the drug with continued administration of
the drug after 3-4 days.

Mechanism of Resistance

Amplification of EGFR gene, gene rearrangements, drug efflux from the cancer cell
cytoplasm are all known mechanisms by which the cancer cell evade effects of Gefitinib [4,
Gefitinib 191

5]. It has been shown [6] that changes in the phospatidyl inositol-3 kinase-Akt pathway as
well as loss of tumour suppressor activity of the PTEN gene both have been identified as
clever ways by which the cancer cell develops resistance. Also subtle coexpression of Her2
has been identified as another possible mechanism of resistance.

Indications

1st line in advanced NSCLC that is EGFR exon 19 deletions or exon 21 (L858R)
substitution mutations as detected by an FDA-approved test [7].

Dosages

It is administered as 250mg once day regimen, usually continuous dosing till progression,
significant toxicity or side effect develops [8].

Methods of Preparation/Administration

Taken orally and comes in once daily regimen [8].

Special Information and Cautions [9, 10]

Contraindications
 Hypersensitivity to the active drug or to its excipients listed below:
 Tablet core
 Lactose monohydrate
 Microcrystalline cellulose (E460)
 Croscarmellose sodium
 Povidone (K29-32) (E1201)
 Sodium lauryl sulfate
 Magnesium stearate
 Tablet coating
 Hypromellose (E464)
 Macrogol 300
 Titanium dioxide (E171)
 Yellow iron oxide (E172)
 Red iron oxide (E172)

Elderly
No dose adjustment.
192 S. Adeleke

Pediatric
Not established safety or efficacy in this population.

Renal Impairment
No dose adjustment if creatinine clearance is >20 ml/min. Caution should be taken if <20
ml/min.

Hepatic Impairment
Moderate to severe hepatic impairment (Child-Pugh B or C) due to cirrhosis show higher
plasmatic concentrations of gefitinib. These patients should be monitored to detect adverse
reactions.
Plasmatic concentrations will not increase in patients with AST, alkaline phosphatase or
bilirubin due to hepatic metastases.

Immunisations
Live vaccines should not be applied while taking the treatment or for at least 6 months
afterwards. Other vaccines can be administered, though may not give as much protection as
usual. In any case, it is safe to be in contact with other people who have had live vaccines as
injections. There can be problems with oral vaccines. Any contacts with someone who has
had oral polio, cholera or typhoid vaccination recently, should be avoided.

Pregnancy
Avoid pregnancy while taking the tablets and at least for two weeks after the last tablet.

Breast-Feeding
This should be avoided while taking the medication.

Warnings

Ocular Disorders
Such as keratitis, aberrant eyelash growth, conjunctivitis, corneal erosion, blepharitis, dry
eye. Stop the treatment for severe or worsening ocular disorders.

Skin Disorders
Though rare, toxic epidermal necrolysis, Stevens Johnson syndrome and erythema
multiforme have been documented. The treatment should be discontinued.

Gastrointestinal Perforation
The treatment should be stopped.

Diarrhoea
Severe or persistent diarrhoea has been documented. Drug should be stopped for up to 14
days.
Gefitinib 193

Interstitial Lung Disease (ILD)


Some few patients may develop ILD, which could be very severe particularly those with
background lung diseases such as COPD, pulmonary fibrosis and in smokers [10].
ILD or ILD-like adverse drug reactions documented are lung infiltration, pneumonitis,
acute respiratory distress syndrome or pulmonary fibrosis. If this is confirmed, gefitinib
should be permanently stopped.

Hepatotoxicity
Increased ALT, AST, and bilirubin have been reported; These should be monitored and
the treatment should be stopped for worsening liver function.

Toxicities [11]

Organic system Very Common Common ≥1/1000 to Uncommon Rare


disorders ≥1/10 <1/10 ≥1/1,000 to (≥1/10.000 a
<1/1000 <1/1.000)
Renal Creatinine elevation, Haemorrhagic
disorders proteinuria, cystitis cystitis
Renal disorders Haematuria, epistaxis
Respiratory, Pulmonary interstitial
thoracic disease
and mediastinal
disorders
Gastrointestinal Diarrhoea, Dehydration Gastrointestinal
disorders vomiting, nausea perforation,
pancreatitis
Hepatobiliary Elevation ALT Elevation AST and Hepatitis
disorders bilirubin
General Asthenia Pyrexia
disorders
Nutritional Anorexia mild to
disorders moderate
Skin and nails Nail changes, alopecia Allergic reactions
disorders (urticarial,
angioedema)
Eye Conjunctivitis, Corneal erosion, Keratitis
disorders blepharitis, dryness aberrant
enlargement of
eyelashes

Dose Modifications [11, 12]

Gefitinib could be stopped for up to 14 days if there are significant toxicities and retried
usually at the same dose.
194 S. Adeleke

Interactions

Drugs which induce cytochrome p450 enzymes may reduce the bioavailability or efficacy
of the drug. Co-administration of drugs like rifampicin, benzodiazepines and phenytoin could
cause reduce bio-availability.
While enzyme inhibitors such as many antibiotics including ciprofloxacin,
sulphonamides and antifungal such as Fluconazole could inhibit the metabolism and
accentuate the effects of drugs [5].

CONCLUSION
Gefitinib is an important drug in treatment of EGFR mutated Adenocarcinoma NSCLC
[11]. It has significantly improved survival in patients who previously used to have few
months to live and often with very poor quality of life. These patients now go on to live
longer albeit with a guarded prognosis depending on factors such as disease burden, patient‘s
pre-morbid state and most importantly, the efficacy of the drug in each individual
circumstance.

REFERENCES
[1] Lung cancer chemotherapy, new treatment and related patents. Recent patents on anti-
cancer drug discovery, Jan 2014, vol. 9, no. 3, p. 372-381 (2014)
[2] Keam B1, Kim DW, Park JH, Lee JO, Kim TM, Lee SH, Chung DH, Heo DS. Rare and
complex mutations of epidermal growth factor receptor, and efficacy of tyrosine kinase
inhibitor in patients with non-small cell lung cancer. Int J Clin Oncol. 2014
Aug;19(4):594-600.
[3] Nguyen KS1, Kobayashi S, Costa DB. Acquired resistance of non-small cell lung
cancer to epidermal growth factor receptor tyrosine kinase inhibitors. Clin Lung
Cancer. 2009 Jul;10(4):281-9.
[4] Nurwidya, Fariz, Takahashi, Fumiyuki, Murakami, Akiko, Kobayashi, Isao, Kato,
Motoyasu, Shukuya, Takehito, Tajima, Ken, Shimada, Naoko, Takahashi, Kazuhisa.
Respiratory investigation, Mar 2014, vol. 52, no. 2, p. 82-91 (March 2014)
[5] Onoda, S. Drug Interaction between Gefitinib and Warfarin. Japanese Journal of
Clinical Oncology. 2005; 35(8):478-482.
[6] Hwang, S., Han, H., Lim, K. and Han, J. Drug Interaction between Complementary
Herbal Medicines and Gefitinib. Journal of Thoracic Oncology. 2008; 3(8):942-943.
[7] Cersosimo, R. Gefitinib: an adverse effects profile. Expert Opinion on Drug Safety.
2006; 5(3):469-479.
[8] Macmillan.org.uk, (2015). Gefitinib (Iressa®) - Cancer Information - Macmillan
Cancer Support [online]. Available at: http://www.macmillan.org.uk/
Cancerinformation/Cancertreatment/Treatmenttypes/Biologicaltherapies/Cancergrowth-
inhibitors/Gefitinib.aspx.
Gefitinib 195

[9] Medicines.org.uk, (2015). Iressa 250mg film-coated tablets - Summary of Product


Characteristics (SPC) - (eMC) [online]. Available at: http://www.medicines.org.uk/
emc/medicine/22104/SPC/.
[10] (Iressa), G. (2015). Gefitinib (Iressa)|Cancer Research UK [online]. Cancerresearchuk.
org. Available at: http://www.cancerresearchuk.org/about-cancer/cancers-in-general/
treatment/cancer-drugs/gefitinib.
[11] Nice.org.uk, (2010). Gefitinib for the first-line treatment of locally advanced or
metastatic non-small-cell lung cancer|Guidance and guidelines|NICE [online].
Available at: http://www.nice.org.uk/guidance/ta192.
[12] Cersosimo, R. Gefitinib: an adverse effects profile. Expert Opinion on Drug Safety,
2006. 5(3), pp. 469-479.
[13] Han J., Lee S., Lee G., Yun T., Lee Y., Hwang K. et al. Phase I/II study of gefitinib
(Iressa®) and vorinostat (IVORI) in previously treated patients with advanced non-small
cell lung cancer. Cancer Chemotherapy and Pharmacology. 2015; 75(3):475-483.
[14] Gil S., Goetgheluck J., Paci A., Broutin S., Friard S., Couderc L. et al. Efficacy and
safety of gefitinib during pregnancy: Case report and literature review. Lung Cancer.
2014; 85(3):481-484.
[15] Passaro A., Di Maio M., Del Signore E., Gori B., de Marinis F. Management of
Nonhematologic Toxicities Associated With Different EGFR-TKIs in Advanced
NSCLC: A Comparison Analysis. Clinical Lung Cancer. 2014; 15(4):307-312.
[16] Sheng Z., Zhang Y. EGFR-TKIs combined with chemotherapy versus EGFR-TKIs
single agent as first-line treatment for molecularly selected patients with non-small cell
lung cancer. Med Oncol. 2014; 32(1).
[17] Mannion E., Waldron D., Gilmartin J. Assessment of lung cancer related symptoms and
treatment related side effects in a group of patients with advanced lung cancer receiving
palliative chemotherapy. Lung Cancer. 2008; 60:S23.
[18] Nishino M., Dahlberg S., Cardarella S., Jackman D., Rabin M., Ramaiya N. et al.
Volumetric tumor growth in advanced non-small cell lung cancer patients with EGFR
mutations during EGFR-tyrosine kinase inhibitor therapy. Cancer. 2013; 119(21):3761-
3768.
[19] Conti A., Santoni M., Amantini C., Burattini L., Berardi R., Santoni G. et al. Progress
of Molecular Targeted Therapies for Advanced Renal Cell Carcinoma. BioMed
Research International. 2013; 2013:1-9.
[20] Engelman J., Zejnullahu K., Mitsudomi T., Song Y., Hyland C., Park J. et al. MET
Amplification Leads to Gefitinib Resistance in Lung Cancer by Activating ERBB3
Signaling. Science. 2007; 316(5827):1039-1043.
In: The Easy Book of Cancer Pharmacology ISBN: 978-1-63485-038-4
Editor: Esther Una Cidon © 2016 Nova Science Publishers, Inc.

Chapter 23

GEMCITABINE. GEMZAR®

P. Martínez del Prado, E. Galve and V. Arrazubi


Medical Oncology Department, Basurto University Hospital, Bilbao, Spain

ABSTRACT
Gemcitabine, difluoro-deoxy-cytidine (dFdC), is a pyrimidine antagonist (an
antimetabolite). It is metabolised intracellularly to active diphosphate and triphosphate
nucleosides which inhibit DNA synthesis. Thus, the cell damage is phase specific.
After intravenous (iv) infusion it is rapidly metabolized by cytidine deaminase in the
liver, kidney, blood and other tissues. This drug displays linear pharmacokinetics.
Systemic clearance depending on gender and age exhibits an inter-individual variability
about 50%. Elimination should be complete within 5 to 11 hours of the start of the
infusion mainly by urine.
This drug is indicated for several metastatic solid tumors as bladder, pancreas, non-
small cell lung cancer (NSCLC), ovarian and breast cancer.
The frequency and severity of the adverse reactions are affected by the dose, infusion
rate and intervals between doses. Dose-limiting toxicities are thrombocytopenia,
leukocytopenia and neutropenia.

Keywords: gemcitabine, antimetabolite, difluoro-deoxy-cytidine

INTRODUCTION
Gemcitabine is a pyrimidine antagonist which is metabolized intracellularly to active
diphosphate and triphosphate nucleosides. Those inhibit DNA synthesis, causing cell damage.
This drug is indicated for several metastatic solid tumors as bladder, pancreas, NSCLC,
ovarian and breast cancer. This drug has got the advantage of being generally well tolerated.
The frequency and severity of the adverse reactions are affected by the dose, infusion rate and


Pilar Martinez del Prado, e-mail: pmdelprado@gmail.com.
198 P. Martínez del Prado, E. Galve and V. Arrazubi

intervals between doses. Dose-limiting toxicities from gemcitabine are thrombocytopenia,


leukocytopenia and neutropenia.

DRUG CLASSIFICATION
Pyrimidine antagonist (an antimetabolite).

MECHANISM OF ACTION
Gemcitabine (dFdC), is a pyrimidine antagonist (an antimetabolite). It is metabolised
intracellularly to active diphosphate (dFdCDP) and triphosphate (dFdCTP) nucleosides which
inhibit DNA synthesis. It exhibits cell phase specificity, primarily killing cells undergoing
DNA synthesis (S-phase) and under certain conditions blocking the progression of cells
through the G1/S phase boundary. There are two mechanisms of action. First, dFdCDP
inhibits ribonucleotide reductase which causes a reduction in the concentration of
deoxynucleosides in general and, in particular, dCTP (deoxycytidine triphosphate, a
nucleoside triphosphate that contains the pyrimide base cytosine). Second, dFdCTP competes
with dCTP for incorporation into DNA (self-potentiation). In addition, a small amount of
gemcitabine may be incorporated into RNA.
DNA polymerase epsilon lacks the ability to eliminate gemcitabine and to repair the
growing DNA strands. After gemcitabine is incorporated into DNA, one additional nucleotide
is added to the growing DNA strands. After this addition there is essentially a complete
inhibition in further DNA synthesis (masked chain termination). Thus, the incorporation of
gemcitabine appears to induce the programmed cell death process known as apoptosis [1].

PHARMACOKINETICS
Absorption
The pharmacokinetics of gemcitabine was obtained for doses ranging from 500
Pharmacokinetics to 2,592 mg/m2 following infusions from 0.4 to 1.2 hours.
Peak plasma concentrations, obtained within 5 minutes of the end of the
infusion, were 3.2 to
 45.5 μg/ml.
Plasma concentrations of the parent compound following a dose of
 1,000
mg/m2/30-minutes are greater than 5 μg/ml for approximately 30-minutes after
the end of the infusion, and greater than 0.4 μg/ml for an additional hour [1]
Distribution The volume of distribution (Vz) of the central compartment was 12.4 l/m2 for
women and 17.5 l/m2 for men with an inter-individual variability of 91.9%.
The Vz of the peripheral compartment was 47.4 l/m2 and it was not sensitive to
gender.
The plasma protein binding was considered to be negligible.
The half-life ranged from 42 to 94 minutes depending on age and gender.
Gemcitabine does not accumulate when administered once weekly [2]
Metabolism Gemcitabine is rapidly metabolized by cytidine deaminase in the liver, kidney,
Gemcitabine. Gemzar® 199

blood and other tissues. The primary metabolite, 2'-deoxy-2', 2'-difluorouridine


(dFdU), is not active and is found in plasma and urine.
Intracellular metabolism of gemcitabine produces the gemcitabine mono, di and
triphosphates (dFdCMP, dFdCDP and dFdCTP) of which dFdCDP and dFdCTP
are considered active.
These intracellular metabolites have not been detected in plasma or urine [2]
Excretion For the recommended dosing schedule, gemcitabine elimination should be
complete within 5 to 11 hours of the start of the infusion.
Systemic clearance (CL) ranged from 29.2 l/hr/m2 to 92.2/hr/m2 depending on
gender and age with an inter-individual variability of 52.2%.
CL for women is approximately 25% lower than the values for men and for both
appears to decrease with age.
At the clinical dose of 1000 mg/m2 given as a 30-minute infusion, lower CL
values should not necessitate a decrease in the gemcitabine dose.
Less than 10% is excreted by the urine as unchanged drug.
 Renal clearance
was 2 to 7 l/hr/m2.
One week after administration, 92 to 98% of the dose of gemcitabine is
recovered, 99% in the urine, mainly in the form of dFdU and 1% of the dose is
excreted in faeces.
Combination therapy with carboplatin and paclitaxel did not alter the
pharmacokinetics of gemcitabine [2]

INDICATIONS [3-9]
 Bladder Cancer

Locally advanced or metastatic bladder cancer in combination with cisplatin.

 Pancreatic cancer

Locally advanced or metastatic adenocarcinoma of the pancreas in monotherapy.

 Non-small cell lung cancer

Locally advanced or metastatic in combination with cisplatin as first line treatment and
can be considered in monotherapy in elderly patients or those with performance status 2.

 Ovarian cancer

Locally advanced or metastatic, in combination with carboplatin, in patients with


relapsed disease following a recurrence-free interval of at least 6 months after platinum-
based, first-line therapy.

 Breast cancer
200 P. Martínez del Prado, E. Galve and V. Arrazubi

In combination with paclitaxel is indicated for the treatment of unresectable, locally


recurrent or metastatic breast cancer who has relapsed following adjuvant/neoadjuvant
chemotherapy. Prior chemotherapy should have included an anthracycline unless clinically
contraindicated.

DOSAGE
 Bladder cancer: Gemcitabine 1000 mg/m2 iv on days 1, 8 and 15 of each 28-day
cycle in combination with cisplatin [4]
 Pancreatic cancer: Gemcitabine 1000 mg/m2 iv, once weekly for up to 7 weeks
followed by a week of rest. Subsequent cycles should consist once weekly for 3
consecutive weeks out of 4 weeks [5]

 NSCLC: In 
monotherapy
 gemcitabine 1000 mg/m2 repeated once weekly for 3


weeks, followed by a 1-week rest period. In combination use dose is 1250 mg/m2 on
day 1 and 8 of the treatment cycle (21 days) [6, 7]
 Breast cancer: Gemcitabine dose of 1250 mg/m2 iv on days 1 and 8 of each 21-day
cycle administered following paclitaxel [8]
 Ovarian cancer: gemcitabine is 1000 mg/m2 on days 1 and 8 of each 21-day cycle iv.
Carboplatin will be given after gemcitabine [9].

METHODS OF PREPARATION/ADMINISTRATION
The diluent for reconstitution of gemcitabine sterile powder is sodium chloride 9 mg/ml
(0.9%) solution for injection (without preservative). The maximum concentration for
gemcitabine upon reconstitution is 40 mg/ml.
The reconstituted solution in-use stability has been demonstrated for 24 hours at 30°C. It
should be used immediately and it should not be refrigerated [3].

SPECIAL INFORMATION AND CAUTIONS


Contraindications

Known hypersensitivity to the active drug or the excipients listed below:

 Macrogol 300
 Propylene glycol
 Anhydrous ethanol
 Sodium hydroxide
 Hydrochloric acid, concentrated acid
Gemcitabine. Gemzar® 201

Elderly Patients

There is no evidence to suggest that dose adjustments are necessary in the elderly
population (>65 years).

Pediatric Patients

It is not recommended for use in children under 18 years of age.

Renal Impairment

There is insufficient information to draw a clear dose recommendation in patients with


renal insufficiency.

Hepatic Impairment

There is insufficient information to draw a clear dose recommendation in patients with


hepatic insufficiency.

Toxicities

Organic disorders Common Uncommon Rare Very rare


(>1/100 to <1/10) (≥1/1000 to (≥1/10,000 to (<1/10,000)
<1/100) <1/1000)
Cardiac disorders Myocardial
infarction,
hypotension
Immunological Anaphylactoid
disorders reaction
Neurological Headache, insomnia,
disorders somnolence
General disorders Anorexia, fever,
chills, astenia,
itching, sweating
Gastrointestinal Diarrhoea, stomatitis
disorders and ulceration of the
mouth, constipation
Blood and Febrile neutropenia Thrombocytosis
lymphatic disorders
202 P. Martínez del Prado, E. Galve and V. Arrazubi

(Continued)

Organic disorders Common Uncommon Rare Very rare


(>1/100 to (≥1/1000 to (≥1/10,000 to (<1/10,000)
<1/10) <1/100) <1/1000)
Investigations Increased Increased gamma-
bilirubin glutamyl
transferase (GGT)
Chest and respiratory Cough, rhinitis Interstitial
disorders pneumonitis,
bronchospasm
(usually mild and

 transient but may
require parenteral
treatment).
Hepatobiliary Increased
disorders bilirubin
Musculoskeletal Back pain,
disorders myalgia
Hair and skin Ulceration Severe skin
disorders Vesicle and sore reactions,
formation, scaling, including
Injection site desquamation
reactions-mainly and bullous skin
mild in nature eruptions
Note: Prolongation of the infusion time and increased dosing frequency has been shown to increase
toxicity [3].
The adverse reactions are affected by the dose, infusion rate and intervals between doses.
Dose-limiting toxicities are reductions in thrombocyte, leucocyte and granulocyte counts.

DOSE MODIFICATION
Bladder, NSCLC and pancreatic cancer, given in monotherapy or in combination with
cisplatin [3].
Dose adjustments during treatment

Absolute granulocyte count Platelet count (x 106/l) Percentage of standard dose of


6
(x 10 /l) Gemcitabine (%)
>1,000 and >100,000 100
500-1,000 or 50,000-100,000 75
<500 or <50,000 Omit dose*
*
Treatment omitted will not be reinstated within a cycle before the absolute granulocyte count reaches
at least 500 (x106/l) and the platelet count reaches 50,000 (x106/l).

Breast cancer, given in combination with paclitaxel [3].


Dose adjustments during treatment
Gemcitabine. Gemzar® 203

Absolute granulocyte count Platelet count (x 106/l) Percentage of standard dose of


(x 106/l) Gemcitabine (%)
> = 1.200 and >75,000 100
1.000< - 1,200 or 50,000-75,000 75
700 - <1000 and > = 50,000 50
<700 or <50.000 Omit dose
*
Treatment omitted will not be reinstated within a cycle. Treatment will start on day 1 of the next cycle
once the absolute granulocyte count reaches at least 1,500 (x10 6/l) and the platelet count reaches
100,000 (x106/l).

Ovarian cancer, given in combination with carboplatin [3].


Dose adjustments during treatment

Absolute granulocyte count Platelet count (x 106/l) Percentage of standard dose


6
(x 10 /l) of Gemcitabine (%)
>1,500 and > = 100,000 100
1.000-1,500 or 75,000-100,000 50
<1000 or <75,000 Omit dose*
*
Treatment omitted will not be reinstated within a cycle. Treatment will start on day 1 of the next cycle
once the absolute granulocyte count reaches at least 1,500 (x10 6/l) and the platelet count reaches
100,000 (x106/l).

For all indications, the gemcitabine dose should be reduced to 75% of the original cycle
initiation dose, in the case of the following haematological toxicities:

 Absolute granulocyte count <500 x 106/l for more than 5 days.


 Absolute granulocyte count <100 x 106/l for more than 3 days.
 Febrile neutropenia.
 Platelets <25,000 x 106/l.
 Cycle delay of more than 1 week due to toxicity.

INTERACTIONS
Radiotherapy

Toxicity associated with concurrent radiotherapy, given together or 7 days apart, is


dependent on many different factors, including dose, frequency of administration, dose of
radiation, radiotherapy planning technique, the target tissue and target volume.
The optimum regimen for safe administration with therapeutic doses of radiation has not
yet been determined in all tumor types.
The data does not indicate any enhanced toxicity when gemcitabine is administered more
than 7 days before or after radiation. Gemcitabine can be started after the acute effects of
radiation have resolved or at least one week after radiation.
Radiation injury has been reported on targeted tissues esophagitis, colitis, and
pneumonitis.
204 P. Martínez del Prado, E. Galve and V. Arrazubi

Live Vaccines

Yellow fever and other live attenuated vaccines are not recommended [3].

CONCLUSION
The safety and efficacy of gemcitabine has been evaluated in phase III trials for different
tumors. In bladder cancer when combined with cisplatin, it changed the standard of care as
similar survival with a better safety profile and tolerability compared to previous MVAC.
Gemcitabine confers a modest survival advantage over treatment with 5-FU and alleviation of
some disease-related symptoms in patients with advanced, symptomatic pancreatic cancer. In
metastatic NSCLC it improved overall survival and the median time to disease progression. In
ovarian cancer it improved the progression-free survival and overall response rate in patients
with relapsed disease following a recurrence-free interval of at least 6 months after platinum-
based first-line therapy. Moreover, this drug is a reasonable choice for women with metastatic
breast cancer in combination with paclitaxel.
Gemcitabine is a drug with a widespread use and good tolerance with manageable
toxicity.

REFERENCES
[1] Plunkett W, Huang P, Gandhi V. Preclinical characteristics of gemcitabine. Anticancer
Drugs [Internet]. 1995 Dec. [cited 2015 Dec 1];6 Suppl. 6:7–13. Available from: http://
www.ncbi.nlm.nih.gov/pubmed/8718419.
[2] Plunkett W, Huang P, Xu YZ, Heinemann V, Grunewald R, Gandhi V. Gemcitabine:
metabolism, mechanisms of action, and self-potentiation. Semin Oncol [Internet]. 1995
Aug. [cited 2015 Dec. 1];22(4 Suppl. 11):–10. Available from: http://www.ncbi.nlm.
nih.gov/pubmed/7481842.
[3] Gemzar. Summary of product characteristics.
[4] von der Maase H, Hansen SW, Roberts JT, Dogliotti L, Oliver T, Moore MJ et al.
Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin
in advanced or metastatic bladder cancer: results of a large, randomized, multinational,
multicenter, phase III study. J Clin Oncol [Internet]. 2000 Sep. [cited 2015 Sep. 22];
18(17):3068–77. Available from: http://www.ncbi.nlm.nih.gov/pubmed/11001674.
[5] Burris HA, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR et al.
Improvements in survival and clinical benefit with gemcitabine as first-line therapy for
patients with advanced pancreas cancer: a randomized trial. J Clin Oncol [Internet].
1997 Jun. [cited 2015 Feb. 23];15(6):2403–13. Available from: http://www.ncbi.nlm.
nih.gov/pubmed/9196156.
[6] Sandler AB, Nemunaitis J, Denham C, von Pawel J, Cormier Y, Gatzemeier U et al.
Phase III trial of gemcitabine plus cisplatin versus cisplatin alone in patients with
locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol [Internet]. 2000
Gemcitabine. Gemzar® 205

Jan. [cited 2015 Dec. 1];18(1):122–30. Available from: http://www.ncbi.nlm.nih.gov/


pubmed/10623702.
[7] Cardenal F, López-Cabrerizo MP, Antón A, Alberola V, Massuti B, Carrato A et al.
Randomized phase III study of gemcitabine-cisplatin versus etoposide-cisplatin in the
treatment of locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol
[Internet]. 1999 Jan. [cited 2015 Dec. 2];17(1):12–8. Available from: http://www.ncbi.
nlm.nih.gov/pubmed/10458212.
[8] Pfisterer J, Plante M, Vergote I, du Bois A, Hirte H, Lacave AJ et al. Gemcitabine plus
carboplatin compared with carboplatin in patients with platinum-sensitive recurrent
ovarian cancer: an intergroup trial of the AGO-OVAR, the NCIC CTG, and the EORTC
GCG. J Clin Oncol [Internet]. 2006 Oct. 10 [cited 2015 Dec. 1];24(29):4699–707.
Available from: http://www.ncbi.nlm.nih.gov/pubmed/16966687.
[9] Albain KS, Nag SM, Calderillo-Ruiz G, Jordaan JP, Llombart AC, Pluzanska A et al.
Gemcitabine plus Paclitaxel versus Paclitaxel monotherapy in patients with metastatic
breast cancer and prior anthracycline treatment. J Clin Oncol [Internet]. 2008 Aug. 20
[cited 2015 Dec. 1];26(24):3950–7. Available from: http://www.ncbi.nlm.nih.gov/pub
med/18711184.
In: The Easy Book of Cancer Pharmacology ISBN: 978-1-63485-038-4
Editor: Esther Una Cidon © 2016 Nova Science Publishers, Inc.

Chapter 24

IMATINIB. GLEEVEC®

A. Ballesteros
Directorate Pharmacist, Oncology,
Poole Hospital Foundation Trust, Poole, UK

ABSTRACT
Imatinib is a synthetic tyrosine kinase inhibitor (TKI) used in the treatment of
chronic myeloid leukaemia (CML) and gastrointestinal stromal tumours (GIST). Phase II
clinical trials have shown significant activity in all phases of CML, but especially in the
chronic phase by inducing complete haematological responses in almost 100% of patients
resistant or intolerant to interferon and a high rate of major cytogenetic response rate [1].
Imatinib is effective and generally well tolerated in patients with Ph+ CML. Imatinib
has also being studied in the palliative setting for metastatic GIST and it also plays a role
as an adjuvant treatment for resectable GIST. Although the ideal duration is not known, it
has been shown to increase the recurrence-free survival in phase III clinical trials [1].

Keywords: imatinib, tyrosine kinase inhibitor, GIST, chronic myeloid leukaemia

INTRODUCTION
Imatinib (Gleevec, Glivec) is a synthetic tyrosine kinase inhibitor (TKI) used in the
treatment of chronic myeloid leukaemia (CML) and gastrointestinal stromal tumours (GIST).
It is specifically designed to inhibit the breakpoint cluster region (BCR)-Abelson (ABL)
fusion protein that results from the chromosomal abnormality known as the Philadelphia
chromosome. Phase II clinical trials have shown significant activity in all phases of CML
[1, 2].
Imatinib is effective and generally well tolerated in these patients but some become
resistant or intolerant and management strategies to overcome these problems include dosage
adjustment, other treatments, or combination with other agents [2].
208 A. Ballesteros

Imatinib has also being studied in the palliative setting for metastatic GIST and now also
plays a role as an adjuvant treatment for resectable GIST as has been shown to increase the
recurrence-free survival in phase III studies. The ideal duration of adjuvant treatment is still
unclear. A multidisciplinary approach is mandatory in these patients [1].

CLINICAL PHARMACOLOGY
Drug Classification

Protein-tyrosine kinase inhibitor [3].

Mechanism of Action [3]

Imatinib is a small molecule protein-tyrosine kinase inhibitor that potently inhibits the
activity of the Bcr-Abl tyrosine kinase (TK), as well as several receptor TKs: Kit, the receptor
for stem cell factor (SCF) coded for by the c-Kit proto-oncogene, the discoidin domain
receptors (DDR1 and DDR2), the colony stimulating factor receptor (CSF-1R) and the
platelet-derived growth factor receptors alpha and beta (PDGFR-alpha and PDGFR-beta).
Imatinib can also inhibit cellular events mediated by activation of these receptor kinases.

Pharmacokinetics [3-5]

Absorption Mean absolute bioavailability 98%


Peak Plasma Time: 2-4 hours
Distribution Binding to plasma proteins was approximately 95%, mostly to albumin and
alpha-acid-glycoprotein, with little binding to lipoprotein.
Metabolism Liver metabolism by cytochrome CYP3A4
Excretion Half-Life: 18 hours (drug) and 40 hours (metabolite)
Clearance: 8-14 L/hour
Excretion: Faeces (68%)
Dialyzable: no

MECHANISM OF RESISTANCE [6]


Mutation on target receptor.
Over-expression of KIT in GIST contributes to imatinib-resistance though the final
mechanism is unclear. p55PIK, an isoform of phosphoinositide 3-kinase (PI3K), increases
KIT expression, and leads to imatinib-resistance in GISTs by activating NF-κB signaling
pathway.
Imatinib. Gleevec® 209

INDICATIONS [3-6]
Chronic Myeloid Leukemia

 Adult and paediatric patients with newly diagnosed Philadelphia chromosome (bcr-
abl) positive (Ph+) chronic myeloid leukaemia (CML) for whom bone marrow
transplantation is not considered as the first line of treatment.
 Adult and paediatric patients with Ph+ CML in chronic phase after failure of
interferon-alpha therapy, or in accelerated phase or blast crisis.
 Adult and paediatric patients with newly diagnosed Philadelphia chromosome
positive acute lymphoblastic leukaemia (Ph+ ALL) integrated with chemotherapy.
 Adult patients with relapsed or refractory Ph+ ALL as monotherapy.

Myelodysplastic/Myeloproliferative Diseases (MDS/MPD)

 Adult patients with myelodysplastic/myeloproliferative diseases (MDS/MPD)


associated with platelet-derived growth factor receptor (PDGFR) gene re-
arrangements.

Hypereosinophilic Syndrome (HES) and/or Chronic Eosinophilic Leukemia


(CEL)

 Adult patients with advanced hypereosinophilic syndrome (HES) and/or chronic


eosinophilic leukaemia (CEL) with FIP1L1-PDGFRα rearrangement.
 The effect of Imatinib on the outcome of bone marrow transplantation has not been
determined.

Kit+ Gastrointestinal Stromal Tumors (GIST)

 The treatment of adult patients with Kit (CD 117) positive unresectable and/or
metastatic malignant gastrointestinal stromal tumours (GIST).
 The adjuvant treatment of adult patients who are at significant risk of relapse
following resection of Kit (CD117)-positive GIST. Patients who have a low or very
low risk of recurrence should not receive adjuvant treatment.

Dermatofibrosarcoma Protuberans (DFSP)

 The treatment of adult patients with unresectable dermatofibrosarcoma protuberans


(DFSP) and adult patients with recurrent and/or metastatic DFSP who are not eligible
for surgery.
210 A. Ballesteros

DOSAGES [3-6]
400mg daily (CML) 400mg daily (GIST).

METHODS OF ADMINISTRATION/PREPARATION [3-6]


Oral route, with a meal and a large glass of water. Doses of 400 mg or 600 mg should be
administered once daily, whereas a dose of 800 mg should be administered as 400 mg twice a
day.
If unable to swallow the film-coated tablets, those should be dispersed in a glass of water
or apple juice. The tablets should be placed in the appropriate volume of liquid
(approximately 50 mL for a 100 mg tablet, and 200 mL for a 400 mg tablet) and stirred with a
spoon. The suspension should be administered immediately after complete disintegration of
the tablet(s).
For dosing of 800 mg and above, dosing should be using the 400 mg tablet to reduce
exposure to iron.
Tablets (scored): 100 mg and 400 mg.

SPECIAL INFORMATION AND CAUTIONS [3-6]


Contraindications

Hypersensitivity to the drug or to its excipients listed below:

 Capsule content
- Microcrystalline cellulose
- Crospovidone
- Magnesium stearate
- Colloidal anhydrous silica

 Capsule shell
- Gelatin
- Red iron oxide (E172)
- Yellow iron oxide (E172)
- Titanium dioxide (E171)

 Printing ink
- Black iron oxide (E172)
- Shellac
Imatinib. Gleevec® 211

Elderly

No differences in the safety or efficacy have been documented in patients older than 65
years as compared to younger.

Pediatric

Safety and efficacy has been established in children with CML. There are no data in
children under 2 years.

Renal Impairment

Dose reductions are necessary for patients with moderate and severe renal impairment.
Doses greater than 600 mg not recommended in mild renal impairment (CrCL = 40-59
mL/min).
Patients with moderate renal impairment (CrCL = 20-39 mL/min): 50% decrease and
increased as tolerated. For patients with moderate renal impairment doses greater than 400 mg
are not recommended.
If severe renal impairment some patients received 100 mg/day and their exposures were
similar to those seen in patients with normal renal function receiving 400 mg/day.

Hepatic Impairment

Patients with mild and moderate hepatic impairment do not require a dose adjustment.
A 25% decrease in the recommended dose should be used for patients with severe hepatic
impairment.

Immunisations

Live vaccines should not be applied while taking the treatment or for at least 6 months
afterwards. Other vaccines can be administered, though may not give as much protection as
usual. In any case, it is safe to be in contact with other people who have had live vaccines as
injections. There can be problems with oral vaccines. Any contacts with someone who has
had oral polio, cholera or typhoid vaccination recently, should be avoided.

Pregnancy

Risk of embryo-fetal toxicity. Pregnancy should be avoided while on the treatment.


212 A. Ballesteros

Breast Feeding

It is not known whether imatinib mesylate or its metabolites are excreted in human milk.
However, breast-feeding is not recommended.

WARNINGS
Cytopenias

Particularly anaemia, neutropenia and thrombocytopenia. Manage with dose reduction or


dose interruption and in rare cases discontinuation of treatment.
A complete blood counts weekly for the first month, biweekly for the second month, and
periodically thereafter are recommended.

Bullous Dermatologic Reactions

Erythema multiforme and Stevens-Johnson syndrome have been reported.

Hypothyroidism

It has been reported in thyroidectomy patients undergoing levothyroxine replacement.


TSH levels should be monitored.

Gastrointestinal Perforation

Some fatal.

Edema and Severe Fluid Retention

Weight patients regularly and manage unexpected rapid weight gain by drug interruption
and diuretics.

Cardiogenic Shock/Left Ventricular Dysfunction

In patients with conditions associated with high eosinophil levels.


Imatinib. Gleevec® 213

Haemorrhage

It has been reported in patients with newly diagnosed CML and with GIST. GI tumor
sites may be the source of GI bleeds in GIST.

Severe Congestive Heart Failure and Left Ventricular Dysfunction

These have been reported, particularly if comorbidities and risk factors.


Patients with cardiac disease or risk factors for cardiac failure should be monitored and
treated.

TOXICITIES [3-6]
System organ Very commo Common Uncommon Rare
class (≥1/10) (≥1/100 to <1/10) (≥1/1000 to <1/100) (≥1/10,000 and
<1/1000)
Sexual Libido decreased
disorders
Eye disorders Eyelid oedema, Eye irritation, eye Cataract, glaucoma, papilloedema
lacrimation pain, orbital
increased, oedema, scleral
conjunctival haemorrhage,
haemorrhage, retinal
conjunctivitis, dry haemorrhage,
eye, blurred vision blepharitis,
macular oedema
Infections and Herpes zoster, herpes simplex, Fungal infection
infestation nasopharyngitis, pneumonia1,
disorders sinusitis, cellulitis, upper
respiratory tract infection,
influenza, urinary tract infection,
gastroenteritis, sepsis
ENT disorders Vertigo, tinnitus, hearing loss
Metabolism and Anorexia Hypokalaemia, increased appetite, Hyperkalaemia,
nutrition hypophosphataemia, decreased hypomagnesaemia
disorders appetite, dehydration, gout,
hyperuricaemia, hypercalcaemia,
hyperglycaemia, hyponatraemia
Nervous system Headache Insomnia, Migraine, somnolence, syncope, Increased intracranial
disorders dizziness, peripheral neuropathy, memory pressure, convulsions,
paraesthesia, taste impairment, sciatica, restless leg optic neuritis
disturbance, syndrome, tremor, cerebral
hypoaesthesia haemorrhage
Psychiatrist Depression, anxiety Confusional state
disorders
Cardiovascular Flushing, Palpitations, tachycardia, cardiac Arrhythmia, atrial
disorders haemorrhage failure congestive, pulmonary fibrillation, cardiac
oedema, hypertension, arrest, myocardial
haematoma, subdural haematoma, infarction, angina
peripheral coldness, hypotension, pectoris, pericardial
Raynaud's phenomenon effusion
214 A. Ballesteros

System organ Very common Common Uncommon Rare


class (≥1/10) (≥1/100 to <1/10) (≥1/1000 to <1/100) (≥1/10,000 and
<1/1000)
Gastrointestinal Nausea, Flatulence, Stomatitis, mouth ulceration, Colitis, ileus,
disorders diarrhoea, abdominal gastrointestinal haemorrhage, inflammatory bowel
vomiting, distension, gastro- eructation, melaena, oesophagitis, disease
dyspepsia, oesophageal ascites, gastric ulcer,
abdominal pain reflux, haematemesis, cheilitis,
constipation, dry pancreatitis
mouth, gastritis
Respiratory Dyspnoea, Pleural effusion, Pleuritic pain,
disorders epistaxis, cough pharyngolaryngeal pain, pulmonary fibrosis,
pharyngitis pulmonary hypertension,
pulmonary haemorrhage
Renal disorders Renal pain, haematuria, renal
failure acute, urinary frequency
increased
Musculoskeletal Muscle spasm Joint swelling Joint and muscle stiffness Muscular weakness,
disorders and cramps, arthritis,
musculoskeletal rhabdomyolysis/myopat
pain including hy
myalgia,
arthralgia, bone
pain
Hepatobiliary Increased hepatic Hyperbilirubinaemia, hepatitis, Hepatic failure, hepatic
disorders enzymes jaundice necrosis
Skin disorders Periorbital Pruritus, face Rash pustular, contusion, Acute febrile
oedema, oedema, dry skin, sweating increased, urticaria, neutrophilic dermatosis
dermatitis/eczema erythema, ecchymosis, increased tendency to (Sweet's syndrome), nail
/rash alopecia, night bruise, hypotrichosis, skin discolouration,
sweats, hypopigmentation, dermatitis angioneurotic oedema,
photosensitivity exfoliative, onychoclasis, rash vesicular, erythema
reaction folliculitis, petechiae, psoriasis, multiforme,
purpura, skin hyperpigmentation, leucocytoclastic
bullous eruptions vasculitis, Stevens-
Johnson syndrome,
acute generalised
exanthematous
pustulosis (AGEP)
Gynaecological Gynaecomastia, erectile Haemorrhagic corpus
disorders dysfunction, menorrhagia, luteum/haemorrhagic
menstruation irregular, sexual ovarian cyst
dysfunction, nipple pain, breast
enlargement, scrotal oedema
Investigations Blood creatinine increased, blood Blood amylase increased
creatine phosphokinase increased,
blood lactate dehydrogenase
increased, blood alkaline
phosphatase increased
Tumour Tumour lysis syndrome
disorders
General Fluid retention Weakness, Chest pain, malaise Haemolytic anaemia
disorders and and oedema, pyrexia, anasarca,
administration fatigue, weight chills, rigors,
site conditions increased weight decreased
Imatinib. Gleevec® 215

System organ Very common Common Uncommon Rare


class (≥1/10) (≥1/100 to <1/10) (≥1/1000 to <1/100) (≥1/10,000 and
<1/1000)
Blood disorders Neutropenia, Pancytopenia, Thrombocytopenia, lymphopenia,
thrombocytopenia, febrile bone marrow depression,
anaemia neutropenia eosinophilia, lymphadenopathy
Unknown
Anaphylactic shock
Cerebral oedema
Vitreous haemorrhage
Pericarditis, cardiac tamponade
Tumour haemorrhage/tumour necrosis
Thrombosis/embolism
Palmoplantar erythrodysesthesia syndrome, lichenoid keratosis, lichen planus, toxic epidermal necrolysis, drug rash with
eosinophilia and systemic symptoms (DRESS)
Avascular necrosis/hip necrosis, growth retardation in children
Renal failure chronic

DOSE MODIFICATIONS [3-6]


Dose adjustments for neutropenia and thrombocytopenia

HES/CEL (starting dose 100 mg) ANC < 1.0 x 109/l 1. Stop Imatinib until ANC ≥ 1.5 x 109/l and
and/or platelets ≥ 75 x 109/l.
platelets < 50 x 109/l 2. Resume treatment with Imatinib at previous
dose (i.e., before severe adverse reaction)
Chronic phase CML, MDS/MPD and GIST ANC < 1.0 x 109/l 1. Stop Imatinib until ANC ≥ 1.5 x 109/l and
(starting dose 400 mg) HES/CEL (at dose and/or platelets ≥ 75 x 109/l.
400 mg) platelets < 50 x 109/l 2. Resume treatment with Imatinib at previous
dose (i.e., before severe adverse reaction).
3. In the event of recurrence of ANC < 1.0 x
109/l and/or platelets < 50 x 109/l, repeat step 1
and resume Imatinib at reduced dose of 300 mg.
Paediatric chronic phase CML ANC < 1.0 x 109/l 1. Stop Imatinib until ANC ≥ 1.5 x 109/l and
(at dose 340 mg/m2) and/or platelets ≥ 75 x 109/l.
platelets < 50 x 109/l 2. Resume treatment with Imatinib at previous
dose (i.e., before severe adverse reaction).
3. In the event of recurrence of ANC < 1.0 x
109/l and/or platelets < 50 x 109/l, repeat step 1
and resume Imatinib at reduced dose of 260
mg/m2.
1. Check whether cytopenia is related to ANC < 0.5 x 109/l 1. Check whether cytopenia is related to
leukaemia (marrow aspirate or biopsy). and/or leukaemia (marrow aspirate or biopsy).
Accelerated phase CML and blast crisis and platelets < 10 x 109/l 2. If cytopenia is unrelated to leukaemia, reduce
Ph+ ALL (starting dose 600 mg) dose of Imatinib to 400 mg.
2. If cytopenia is unrelated to leukaemia, 3. If cytopenia persists for 2 weeks, reduce
reduce dose of Imatinib to 260 mg/m2. further to 300 mg.
3. If cytopenia persists for 2 weeks, reduce 4. If cytopenia persists for 4 weeks and is still
2
further to 200 mg/m . unrelated to leukaemia, stop Imatinib until ANC
4. If cytopenia persists for 4 weeks and is still ≥ 1 x 109/l and platelets ≥ 20 x 109/l, then
unrelated to leukaemia, stop Imatinib until resume treatment at 300 mg.
ANC ≥ 1 x 109/l and platelets ≥ 20 x 109/l,
then resume treatment at 200 mg/m2.
DFSPaANC < 0.5 x 109/l ANC < 1.0 x 109/l 1. Stop Imatinib until ANC ≥ 1.5 x 109/l and
(at dose 800 mg) and/or platelets ≥ 75 x 109/l.
and/or platelets < 50 x 109/l 2. Resume treatment with Imatinib at 600 mg.
platelets < 10 x 109/l 3. In the event of recurrence of ANC < 1.0 x
Paediatric accelerated phase CML and blast 109/l and/or platelets < 50 x 109/l, repeat step 1
2 and resume Imatinib at reduced dose of 400 mg.
crisis (starting dose 340 mg/m )
ANC = absolute neutrophil count
occurring after at least 1 month of treatment
216 A. Ballesteros

Dose Modifications in Hepatic Impairment


If bilirubin >3xULN or liver transaminases >5X ULN withhold imatinib until bilirubin <
1.5 x ULN or liver transaminases < 2.5 xULN.
Treatment can be continued at a reduced dose:

In adults- 400 mg od →300 mg od; 600 mg od → 400 mg od, 800 mg od → 600 mg od.

In children from 340 to 260mg/m2/day.


Patients with mild/moderate/severe impairment should be given the minimum
recommended dose of 400mg/day and this should be reduced if it is not tolerated.

INTERACTIONS [3-7]
Substances that alter the stomach's pH will influence into how much imatinib is absorbed.
Medications that should not be taken with Gleevec are warfarin, erythromycin and
phenytoin.
Patients should also avoid grapefruit juice and other foods known to inhibit CYP3A4
while taking Gleevec.
Caution with protease inhibitors, antifungal medications.
Risk of therapeutic failure if concomitant use with CYP3A4 inductors such as
dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbital, Hypericum
perforatum.

CONCLUSION
Imatinib (Gleevec, Glivec) is a synthetic tyrosine kinase inhibitor (TKI) used in the
treatment of chronic myeloid leukaemia (CML) and gastrointestinal stromal tumours (GIST).
It is specifically designed to inhibit the breakpoint cluster region (BCR)-Abelson (ABL)
fusion protein that results from the chromosomal abnormality known as the Philadelphia
chromosome. Phase II clinical trials have shown significant activity in all phases of CML
[3-7].
Imatinib is effective and generally well tolerated in these patients but some become
resistant or intolerant and management strategies to overcome these problems include dosage
adjustment, other treatments, or combination with other agents [3-7].
Imatinib has also being studied in the palliative setting for metastatic GIST and now also
plays a role as an adjuvant treatment for resectable GIST as has been shown to increase the
recurrence-free survival in phase III studies. The ideal duration of adjuvant treatment is still
unclear. A multidisciplinary approach is mandatory in these patients. Neoadjuvant imatinib
can be considered for initially unresectable tumor or if a downsizing of the tumor would
allow resection with decreased surgical morbidity [3-7].
Imatinib. Gleevec® 217

REFERENCES
[1] Isabelle Deshaies, Jovenel Cherenfant, Niraj J Gusani, Yixing Jiang, Harold A Harvey,
Eric T Kimchi, Jussuf T Kaifi, Kevin F Staveley-O‘Carroll. Gastrointestinal stromal
tumor (GIST) recurrence following surgery: review of the clinical utility of imatinib
treatment. Ther Clin Risk Manag. 2010; 6: 453–458.
[2] Melo JV, Chuah C. Resistance to imatinib mesylate in chronic myeloid leukaemia.
Cancer Lett. 2007 8;249(2):121-32.
[3] Imatinib-Medscape Reference. http://reference.medscape.com/drug/gleevec-imatinib-
342239.
[4] Gleevec (imatinib mesylate) tablets Label - Food and Drug Administration.
http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021588s024lbl.pdf.
[5] Glivec, INN-imatinib - Europa http://www.ema.europa.eu/docs/es_ES/document_
library/EPAR_-_Product_Information/human/000406/WC500022207.pdf.
[6] Lai S, Wang G, Cao X, Luo X, Wang G, Xia X, Hu J, Wang J. KIT over-expression by
p55PIK-PI3K leads to Imatinib-resistance in patients with gastrointestinal stromal
tumours. Oncotarget. 2015;22. doi: 10.18632/oncotarget.6011.
[7] Haouala A, Widmer N, Duchosal MA, Montemurro M, Buclin T, Decosterd LA. Drug
interactions with the tyrosine kinase inhibitors imatinib, dasatinib, and nilotinib. Blood
2010.
In: The Easy Book of Cancer Pharmacology ISBN: 978-1-63485-038-4
Editor: Esther Una Cidon © 2016 Nova Science Publishers, Inc.

Chapter 25

IPILIMUMAB

J. Fra
Oncology Unit, University Hospital Río Hortega, Valladolid, Spain

ABSTRACT
Recently new anticancer drugs have been developed as increased understanding of
how the immune system interacts with a tumour and its microenvironment has led to the
identification of novel targets as potential new immunotherapies. In this context, the
approval of ipilimumab against melanoma represents a significant step forward in cancer
immunotherapy [1-3].
The clinical use of this drug seems to be challenging as requires careful monitoring
and prompt treatment of side-effects. The most striking data with ipilimumab are those
showing a small but significant number of patients surviving 2 and 3 years from the
treatment initiation. Further research is needed to draw a final conclusion regarding
potential predictive markers of response to this treatment which would help identify the
patients who should be treated with this drug [4, 5].

Keywords: ipilimumab, immunotherapy, anti-CTLA-4

INTRODUCTION
Ipilimumab is a fully human anti-cytotoxic T-lymphocyte antigen-4 monoclonal antibody
that potentiates antitumor T-cell responses. This new agent has demonstrated to improve
survival in previously treated and treatment-naïve patients with unresectable stage III and IV
melanoma. This benefit has also been shown in those patients with brain metastases.
Ipilimumab can induce novel response patterns for which immune-related response criteria
have been designed. Side-effects with this drug are common but generally low grade though
severe and life-threatening side effects have been also documented.


Joaquin Fra, e-mail: jfrar@seom.org.
220 J. Fra

CLINICAL PHARMACOLOGY [6]


Drug Type

Fully human anti-cytotoxic T-lymphocyte antigen-4 monoclonal antibody.

Mechanism of Action

Ipilimumab is a monoclonal fully human antibody (IgG1κ) anti-CTLA-4. CTLA-4 is a


molecule involved in the negative regulatory system of lymphocyte activation. Ipilimumab
specifically blocks the inhibitory signal of CTLA-4, leading to the activation and proliferation
of T-lymphocytes. Activation of cytotoxic action of these immune cells makes infiltration of
tumours by lymphocytes, and it leads to the death of malignant cells.
The mechanism of action of Ipilimumab is indirect, unlike others of new anti-tumour
monoclonal antibodies, which act on the mechanisms of tumour growth. Ipilimumab
enhances the immune response of the body against malignant cells, therefore it is not a
mechanism of action directed specifically against any type of specific tumour, what makes it
potentially effective in any type of cancer.

Pharmacokinetics

Absorption In one pharmacokinetic study of patients with unresectable or metastatic


melanoma peak concentrations, trough concentrations, and area under the
curve (AUC) were found to be dose proportional in the dosage range
examined (0.3, 3, or 10 mg/kg every 3 weeks for four doses).
Distribution Volume of distribution at steady state = 7.21 L
Metabolism Degradation into small peptides and amino acids and undergo excretion via
normal protein catabolism.
Excretion Clearance was 15.3 mL/hr-16.8 mL/hr.
A pharmacokinetic study examining ipilimumab every 3 weeks, clearance
was time invariant. Minimal systemic accumulation was observed
(accumulation index of 1.5 fold or less). Steady state concentration was
reached by the third dose.
Terminal Elimination Half-life: 14.7-15.4 days.

Indications

Ipilimumab is approved in Europe only for the treatment, in monotherapy, of adult


patients with advanced melanoma (unresectable or metastatic). Initially approved for patients
that they had received at least one prior treatment, but its use in first-line of treatment has
recently been approved.
Ipilimumab 221

Dosage

The standard treatment with Ipilimumab is 3 mg/kg administered iv over a period of 90


minutes every three weeks, with a total of 4 doses. Patients should receive the entire induction
regime (4 doses) unless not tolerate it, regardless of the appearance of new lesions or the
growth of existing lesions.
It is not necessary adjustment of dose in the elderly. There are no data for safety of
Ipilimumab in persons under the age of 18 years. It is not necessary dose adjustment in
patients with mild or moderate renal insufficiency known prior to treatment, nor with pre-
existing mild liver failure. Should be administered with caution in patients with moderate or
severe hepatic failure (transaminases ≥5 x ULN or bilirubin levels >3 x ULN).
In case of adverse events for Ipilimumab is not recommended dose reduction. Depending
on the severity of the toxicity and the time that takes to forward, delay or suspend a dose, or
definitely suspend the treatment, will be raised.

Methods of Preparation/Administration

Ipilimumab is presented as a concentrated solution (5 mg/ml) for infusion. Is a clear to


slightly opalescent, colourless to pale yellow liquid. It may contain a few light particles. It has
a pH of 7.0 and an osmolality of 260-300 mOsm/kg.
It can be used for intravenous (iv) administration without dilution, but usually diluted in a
solution to reach a concentration between 1 and 4 mg/ml. Dilution can be used an injectable
solution of sodium chloride 9 mg/ml (0.9%) or glucose 50 mg/ml (5%). To contain the
dilution bottles of sterile glass, PVC or PVC-free bags, can be used.
The preparation of dilution for infusion should be through an aseptic manipulation. To do
this use a flow hood laminar or a safety cab, using standard precautions for the safe handling
of iv agents.
Ipilimumab should not be administered as an iv bolus injection. The recommended
infusion time is 90 minutes. It cannot be infused at the same time by the same iv line with
other agents; in this case use a separate line for the perfusion of Ipilimumab. After perfusion
is necessary to clean the line with injectable solution of sodium chloride 9 mg/ml (0.9%) or
glucose 50 mg/ml (5%).
An equipment of perfusion and an inline filter sterile, non-pyrogenic, of low protein
binding must be used for iv infusion. Perfusion equipment should be of PVC, and filters on
line of polyethersulfone (0.2 µm to 1.2 µm) or nylon (0.2 μm).
Tumour response evaluations should be performed only once completed induction
therapy after four cycles. It does not approved maintenance dose, but a new induction of 4
cycles can be done when the tumour progresses after having obtained a lasting improvement
of the disease.
222 J. Fra

Special Informations and Cautions [6]

Contraindications
Hypersensitivity to the active drug or to its excipients listed below:

 Tris hydrochloride (2-amino-2-hydroxymethyl-1,3-propanediol hydrochloride)


 Sodium chloride
 Mannitol (E421)
 Pentetic acid (dietilenitriaminopentaacético acid)
 Polysorbate 80
 Sodium hydroxide (for pH adjustment)
 Hydrochloric acid (pH adjustment)
 Water for injections

Elderly
Dose adjustment is not needed.

Pediatric
It should not be used in children younger than 18 years until more data are available.

Renal Impairment
Safety and efficacy has not been studied in this population but pharmacokinetic data
suggest that no dose adjustment is needed if mild to moderate renal impairment.

Hepatic Impairment
If mild hepatic impairment no dose adjustment is needed.
Caution should be applied if transaminases ≥5 x UNL or bilirubin >3 x UNL.

Immunisations
Live vaccines should not be applied while taking the treatment or for at least 6 months
afterwards. Other vaccines can be administered, though may not give as much protection as
usual. In any case, it is safe to be in contact with other people who have had live vaccines as
injections. There can be problems with oral vaccines. Any contacts with someone who has
had oral polio, cholera or typhoid vaccination recently, should be avoided.

Pregnancy
Unknown risk for the fetal development. Recommended effective contraception while on
the treatment.

Breast-Feeding
Unknown if ipilimumab is excreted in maternal milk, but due to the potential adverse
effects in the baby, it is advisable to stop nursing while on the treatment.
Ipilimumab 223

Warnings

Immune-Mediated Adverse Reactions


Severe and fatal immune-mediated side-effects due to T-cell activation and proliferation
may involve any organ system. The most frequent ones are enterocolitis, hepatitis, dermatitis
(including toxic epidermal necrolysis), neuropathy and endocrinopathy.
Others include encephalitis, neurosensory hypoacusis, myositis, polymyositis, ocular
myositis and sarcoidosis. These reactions typically manifest during treatment but may occur
weeks to months after discontinuation.
If severe immune-mediated reactions occur, permanently discontinue and initiate
systemic high-dose corticosteroid therapy.
Monitor signs and symptoms of enterocolitis, neuropathy, dermatitis and endocrinopathy.
The majority of these immune-mediated reactions initially manifested during treatment.
A minority occurred weeks to months after discontinuation of Ipilimumab. They must be
evaluated at baseline and before each dose clinical chemistries, including liver function tests
and thyroid function tests.

Toxicity [6]

Organic system Very Common Common Uncommon Rare (≥1/10.000


disorders ≥1/10 ≥1/1000 to <1/10 ≥1/1,000 to <1/1000 a <1/1.000)
Infections and Sepsis, UTI, septic shock,
Infestations disorders respiratory infection
Related to the cancer Tumoral pain Paraneoplastic syndrome
Immunological Hypersensitivity Anaphylactic
disorders shock
Endocrine disorders Hypopituitarism Adrenal insufficiency, Autoimmune
(hypophysitis), hypogonadism thyroiditis,
hypothyroidism hyperthyroidism thyroiditis
Nervous system Headache, Guillain-Barre syndrome, Myasthenia
disorders dizziness, lethargy,meningitis, encephalitis, gravis
peripheral sensitivesyncopal, craneal
neuropathy neuropathy, cerebral
oedema, peripheral
neuropathy, ataxia, tremor,
myoclonias, dysarthria
Blood and lymphatic Anaemia, Haemolytic anaemia,
system disorders lymphopenia thrombocytopenia,
eosinophilia, neutropenia
Eye disorders Ocular pain, blurry Uveitis, vitreal
vision haemorrhage, iritis, ocular
oedema, blepharitis, visual
reduction, conjunctivitis,
foreign body in the eye
Renal and urinary Renal insufficiency, tubular Proteinuria
disorders acidosis, haematuria,
autoimmune
glomerulonephritis
224 J. Fra

(Continued)

Organic system Very Common Common Uncommon Rare (≥1/10.000


disorders ≥1/10 ≥1/1000 to <1/10 ≥1/1,000 to <1/1000 a <1/1.000)
Respiratory, thoracic Dyspnea, cough Respiratory insufficiency,
and mediastinal acute respiratory distress,
disorders pulmonary infiltration or
oedema, pneumonitis,
allergic rhinitis
Gastrointestinal Vomiting, Gastrointestinal Gastrointestinal perforation, Proctitis
disorders nausea, haemorrhage, colonic perforation,
diarrhoea colitis, gastroenteritis, peritonitis,
constipation, diverticulitis, pancreatitis,
gastroesophageal enterocolitis, oesophagitis,
reflux, abdominal ileus, colonic ulcer
pain, mucositis
Hepatobiliary Hepatic Hepatic insufficiency,
disorders impairment hepatitis, hepatomegaly,
jaundice
Skin and Eruption, Dermatitis, Toxic epidermic necrolysis, Erythema
subcutaneous tissue itchiness urticaria, eczema, leucocytoclastic vasculitis, multiformed,
disorders vitiligo, erythema, exfoliation skin, changes in psoriasis
alopecia, night hair coloring, drug reaction
sweats, dry skin with eosinophilia and
systemic ymptoms or
DRESS syndrome
Cardiovascular Hypotension, hot Arrhythmia, atrial Temporal
disorders flushes, blush fibrillation, vasculitis, arteritis
angiopathy, orthostatic
hypotension, peripheral
ischaemia
Investigations Elevation of ALT, Elevation of GGT, Reduction of
AST, alkaline creatinine, TSH, reduction TSH and
phosphatase, cortisol, lipase, amylase, thyroxin,
bilirubin, weight- ANA, testosterone prolactin
loss
Musculoskeletal and Arthralgias, Polymyalgia, myositis, Polymyositis
connective tissue myalgias, arthritis, muscular weakness
disorders musculoskeletal
pain, muscular
spasms, rheumatic
General disorders and Fatigue, local Shivers, pain, Infusion reaction,
administration site reaction, oedema, flu-like multiorganic syndrome,
conditions pirexia syndrome systemic inflammatory
syndrome
Psychiatric disorders Confusion Changes in mental status,
depression, decreased libido
Metabolism and Anorexia Hypokalemia, Hyponatremia,
nutrition disorders dehydration hypophosphatemia, tumoral
lysis, hypocalcemia
Ipilimumab 225

The majority of drug-related adverse effects (AE) were inflammatory nature, caused by
the immune effect of the medication (immune-mediated or immuno-related AE) [7, 8].
Typically were of moderate or low grade. Normally they could be reversed with
symptomatic or corticosteroid medication oral. However Ipilimumab treatment-related
adverse effects can be severe and even fatal.

Interactions

Ipilimumab is not metabolised by the cytochrome P450 (CYP). No interactions have been
seen between ipilimumab and paclitaxel/carboplatin, dacarbazine or its metabolite.

Steroids
Avoid systemic steroids before starting ipilimumab as they may counteract its activity.
However, these could be used to treat immune adverse reactions.
Its use after having commenced ipilimumab seems not to alter its efficacy.

Anticoagulants
Ipilimumab can produce gastrointestinal haemorrhage and anticoagulants can increase the
risk. Monitor carefully.

CONCLUSION
Ipilimumab has been a remarkable step forward in the treatment of patients with
advanced melanoma. The main highlight of this treatment is the possibility of getting a much
more prolonged tumour response as expected with classic patterns for chemotherapy.
However the low percentage of patients who get tumour response, the risk of severe, and
even fatal, adverse effects along with the high cost of the treatment, have been obstacles so
that the drug has not been used more widely.
Currently most effective ways to optimize the results of this treatment are being
investigated. Among other research, the most promising results include combinations with
other antibody with immuno-modulator effect [9]. This, or other combinations, could be the
next step forward in the treatment of patients with advanced melanoma.

REFERENCES
[1] Berman D, Korman A, Peck R, Feltquate D, Lonberg N, Canetta R. The development
of immunomodulatory monoclonal antibodies as a new therapeutic modality for cancer:
The Bristol-Myers Squibb experience. Pharmacology and Therapeutics. 2015; 148:
132-53.
[2] Wolchok JD, Neyns B, Linette G, Negrier S, Lutzky J, Thomas L et al. Ipilimumab
monotherapy in patients with pretreated advanced melanoma: a randomised, double-
blind, multicentre, phase 2, dose-ranging study. Lancet Oncol. 2010; 11(2): 155-64.
226 J. Fra

[3] O‘Day SJ, Maio M, Chiarion-Sileni V, Gajewski TF, Pehamberger H, Bondarenko IN


et al. Efficacy and safety of ipilimumab monotherapy in patients with pretreated
advanced melanoma: a multicenter single-arm phase II study. Ann Oncol. 2010; 21(8):
1712-7.
[4] Hodi FS, O‘Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB et al.
Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J
Med. 2010; 363(8): 711-23.
[5] Wolchok JD, Hoos A, O‘Day SJ, Weber JS, Hamid O, Lebbé C et al. Guidelines for the
evaluation of immune therapy activity in solid tumors: immune-related response
criteria. Clin Cancer Res. 2009; 15: 7412-20.
[6] Yervoy, INN-ipilimumab - Europa. http://www.ema.europa.eu/docs/es_ES/document_
library/EPAR_-_Product_Information/human/002213/WC500109299.pdf.
[7] Lebbe C, O‘Day SJ, Chiarion Sileni V, Gajewski TF, Pehumberger H, Bondarenko IN
et al. Analysis of the onset and resolution of immune-related adverse events during
treatment with ipilimumab in patients with metastatic melanoma. Perspectives in
Melanoma XII, Amsterdam, 2008, October 2-4, Abstract O.015.
[8] Ibrahim RA, Berman DM, DePril V, Humphrey RW, Chen T, Messina M et al.
Ipilimumab safety profile: summary of findings from completed trials in advanced
melanoma. J Clin Oncol. 2011; 29 (Suppl. 15) (Abstract 8583).
[9] Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM et al.
Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013; 369: 122-33.
In: The Easy Book of Cancer Pharmacology ISBN: 978-1-63485-038-4
Editor: Esther Una Cidon © 2016 Nova Science Publishers, Inc.

Chapter 26

IRINOTECAN.CPT-11. CAMPTOSAR®

E. Una Cidon
Medical Oncology Department, Royal Bournemouth Hospital NHS Foundation Trust,
Bournemouth, UK

ABSTRACT
Camptothecins are broad-spectrum anticancer drugs that specifically target DNA
topoisomerase I (Topo I) [1]. Irinotecan belongs to these drugs and it is a semisynthetic
analog of camptothecin, originally isolated from the Chinese/Tibetan ornamental tree
Camptothecaacuminata [2]. Itsactivity is due to rapid formation of an in vivo active
metabolite, SN-38 [3]. The formation of a cleavable drug-Topo I-DNA complex leads to
a lethal double-strand DNAbreakage and cell death. Preclinical studies suggest that the
drug's antitumor and toxic effects may be schedule-dependent. Preliminary antitumor
activity studied inleukemia and lymphoma supports this theory. It was first discovered
andsynthesized in Japan in 1983, and it has shownpotent antitumor activity against a wide
range of tumors [2]. Unfortunately, resistance to this drug is common and several studies
have been performed to show possiblemechanisms and use some biological modulation
to resolve it.

Keywords: irinotecan, topoisomerase I, camptothecins

INTRODUCTION
Irinotecan has shown activity against many kind of tumors such as colorectal, esophageal,
gastric, non-small-cell and small-cell lung cancers, leukemia and lymphomas, as well as
central nervous system malignant gliomas [2]. Initially approved in 1998 for second-line
treatment of metastatic colorectal cancer, after failure of 5-fluorouracil (5-FU) and leucovorin
[2], and more recently it has been approved for use in combination with 5-FU/leucovorin as a


E. Una Cidon, aunacid@hotmail.com; Esther.unacidon@rbch.nhs.uk.
228 E. Una Cidon

first-line treatment for this disease [2]. Its main toxicities for all of the administration
schedules are diarrhea and neutropenia.
Several studies have assessed irinotecan as adjuvant chemotherapy innode-positive
colorectal cancer after resection but have failed to support irinotecan-based regimens as
adjuvant therapy.

CLINICAL PHARMACOLOGY
Drug Classification [4, 5]

It is a Topo I inhibitor which belongs to camptothecins family.

Pharmacokinetics [4, 5]

Absorption Biphasic or triphasicelimination.


Mean plasmatic clearance 15 l/h/m2
Maximum concentrations of SN-38 seen within1 hour following the end of a 90-
minute infusion of irinotecan.
Plasmatic concentrations of irinotecan and SN-38 at the end of the infusion were 7,7
μg/ml y de 56 ng/ml
Mean AUC 34 μg.h/ml y de 451 ng.h/ml respectively.
Distribution Distribution volume 157l/m2
Moderate plasma protein binding (30-68% bound).
SN-38 ishighly bound to human plasma proteins (95% bound).
Albumin is the plasma proteinto which irinotecan and SN-38 predominantly binds.
Plasmatic half-life of first phase of triphasic model is 12 minutes, second phase 2.5
hours and terminal phase 14.2 hours.
SN-38 biphasic elimination, half-life elimination 13.8 hours.
Metabolism Conversion of irinotecan to SN-38 mediated by carboxylesterase enzymes.
It primarily occurs in theliver.
SN-38 is subsequently conjugated predominantly by the enzyme UDP-
glucuronosyltransferase 1A1 (UGT1A1) to form a glucuronide metabolite.
Excretion Elimination half-life of irinotecan is 6-12 h.
Elimination half-life of SN-3810-20 h.
Urinary excretion of irinotecan is 11-20%, SN-38 is<1%; and SN-38 glucuronide is
3%.

Mechanisn of Resistance [1-3]

Resistance to the camptothecins is common (de novo or acquired clinical resistance).


Several studies have suggested the following mechanisms of resistance:
Irinotecan.CPT-11. Camptosar® 229

1) Variable levels of the enzymes involved in the conversion of irinotecan


2) Reduced levels of Topo I expression or alteration in its structure from different
mutations
3) Reduced cellular accumulation from active drug efflux
4) Alterations in the cellular response to camptothecin-Topo I-DNA complex formation,
which involves proteasome degradation of Topo I and/or enhancedDNA repair
5) Activation of the nuclear factor kappa B by DNA damage and consequent
suppression of apoptosis.

Indications [4, 5]

Irinotecan is indicated as a first-line therapy in combination with 5-FU/LV for patients


with metastatic carcinoma ofthe colon or rectum.
It is also indicated for patients with metastatic carcinoma of the colon or rectum whose
disease has recurred or progressed following initial 5-FU-based therapy.

Dosages [4, 5]

Single Agent
Weekly regimen
125 mg/m2 intravenously (iv) over 90 minutes, day 1, 8, 15, 22. Then 2 weeks rest.
Modification:
Dose level 1 100 mg/m2
Dose level 2 75 mg/m2
Subsequent doses will be adjusted in 25 to 50 mg/m2 decrements depending on individual
tolerance as low as 50 mg/m2.
Once every three weeks.
350 mg/m2iv over 30 to 90 minutes, once every 3 weeks.
Modification:
Dose level 1 300 mg/m2
Dose level 2 250 mg/m2
Subsequent doses will be adjusted in 50 mg/m2 decrements depending on individual
tolerance as low as 200 mg/m2.

Combination
Recommended dose of irinotecan is 180mg/m2 every two weeks over 30 to 90 minutes
followed by LV and 5-FU.
230 E. Una Cidon

METHODS OF PREPARATION/ADMINISTRATION
Special Information and Cautions [4, 5]

Contraindications
Irinotecan is contraindicated if known hypersensitivity to the drug or the excipients. It is
also contraindicated if bilirubin levels are >3 upper normal limit (UNL) or ECOG
performance status is 3 or above and concomitant use of hypericum (St John‘s wort) and
ketoconazole.

Elderly Patients
There are no pharmacological studies in elderly but patients older than 65 years of age
should be closely monitored as greater risk of late diarrhoea in this population. The starting
dose of irinotecan for patients 70 years and older for the once-every-3-week-dosage schedule
should be 300 mg/m2.

Pediatric Patients
The effectiveness of irinotecan in pediatric patients has not been established. Results
from several studies have shown that the adverse event profile was comparable to that in
adults.
Minimal accumulation of SN-38 was observed in children on daily dosing regimens.

Renal Impairment
Irinotecan is not recommended in patients with renal impairment as no studies have been
carried out in this population.

Hepatic Impairment
The influence of hepatic insufficiency on the pharmacokinetic of irinotecan and its
metabolites has not been studied. Among patients with known hepatic tumor involvement (a
majority of patients), irinotecan and SN-38 AUC values were higher than values for patients
without liver metastases.
Bilirubin levels should be taken into account to decide what should be the first dose of
irinotecan.

Bilirubin levels Dose of irinotecan


<1.5 UNL 350 mg/m2
1.5-3 UNL 200 mg/m2
>3 UNL Not indicated

There are no data for patients with hepatic impairment treated with irinotecan in
combination.

Immunisations
Live vaccines should not be applied while taking the treatment or for at least 6 months
afterwards. Other vaccines can be administered, though may not give as much protection as
Irinotecan.CPT-11. Camptosar® 231

usual. In any case, it is safe to be in contact with other people who have had live vaccines as
injections. There can be problems with oral vaccines. Any contacts with someone who has
had oral polio, cholera or typhoid vaccination recently, should be avoided.

Warnings [4, 5]

Diarrhoea (Early and Late)


Irinotecan can induce both early and late forms ofdiarrhoea that are mediated by different
mechanisms. Both forms of diarrhoea may be severe.
Early diarrhoea (occurring during or shortly after infusion of Irinotecan) may be
accompanied by cholinergic symptoms of rhinitis, increased salivation, miosis, lacrimation,
diaphoresis, flushing, and intestinal hyperperistalsis that can causeabdominal cramping. Early
diarrhea and other cholinergic symptoms may be prevented or ameliorated by atropine.
Late diarrhoea (generally occurring more than 24 hours after administration of irinotecan)
can be life threatening since it may be prolonged and may lead to dehydration, electrolyteim
balance or sepsis. Late diarrhoea should be treated promptly with loperamide. Patients with
diarrhoea should be carefully monitored and given fluid and electrolyte replacement if they
become dehydrated or antibiotic therapy if they develop ileus, fever, or severe neutropenia.
Administration of irinotecan should be interrupted and subsequent doses reduced if severe
diarrhea occurs.

Myelosuppression
Severe myelosuppression may occur.

Pregnancy
Women should be advised to avoid becoming pregnant while receiving treatment with
irinotecan. Effective anticonceptive methods should be used while on treatment.
Irinotecan can cause fetal harm when administered to a pregnant woman.

Breastfeeding
It is unknown whether the irinotecan is excreted in maternal milk and this is the reason to
advice not to breastfeed if receiving this treatment.

Gilbert Syndrome
Patients with deficient glucuronidation of bilirubin, such as those with Gilbert‘s
syndrome, may be at greater risk of myelosuppression when receiving therapy with
irinotecan.

Extravasation
Irritant agent. If an extravasation occurs, flushing the site with sterile water and
applications of ice are recommended.
232 E. Una Cidon

INTERACTIONS [4, 5]
CYP3A4 Enzyme-Inducers

Anticonvulsants
These drugs will reduce exposure to irinotecan and SN-38 as CYP3A4 enzyme-inducing
(phenytoin, phenobarbital orcarbamazepine).
The appropriate starting dose for these patients has not yet been defined.
A consideration should be given to replacing non-enzyme inducing anticonvulsants at
least 2 weeks prior to initiation of irinotecan therapy.

Antibiotics
Such as rifampin and rifabutin.

St. John’s Wort


Exposure to the active metabolite SN-38 is reduced in patients receiving concomitant
St.John‘s Wort. St. John‘s Wort should be discontinued at least 2 weeks prior to thefirst cycle
of irinotecan, and it is contraindicated during irinotecan therapy.

5-FU/Leucovorin (LV)
In a phase 1 clinical study involving irinotecan combined with 5-FU/LV, the disposition
of irinotecan or SN-38 was not substantially modified.
Formal drug interaction studies to evaluate the influence of irinotecan on the disposition
of 5-FU and LV have not been conducted.

Dexamethasone
It does not appear to alter the pharmacokinetics of irinotecan.

Ketoconazole
Ketoconazole is a strong inhibitor of CYP3A4. Patients receiving concomitant
ketoconazole have increased exposure to irinotecan and SN-38. Patients should discontinue
ketoconazole at least 1 weekprior to starting irinotecan therapy and it is contraindicated
during irinotecan therapy.

Toxicities [4, 5]

Organic disorders Very common Common Uncommon Rare


≥1/10 ≥1/100 and <1/10 ≥1/1000 and ≥1/10,000 and
<1/100 <1/1000
Hair and skin Alopecia Cutaneous reactions
disorders
Cardiovascular Hypotension (due to Hypertension
disorders dehydration),
cardiovascular
insufficiency
Irinotecan.CPT-11. Camptosar® 233

Organic disorders Very common Common Uncommon Rare


≥1/10 ≥1/100 and <1/10 ≥1/1000 and ≥1/10,000 and
<1/100 <1/1000
Metabolic and Dehydration Anorexia
nutrition disorders
General disorders Fever (in absence Intense fatigue,
of infection or cholinergic
severe syndrome
neutropenia)
Gastrointestinal Diarrhoea, Mucositis, Gastrointestinal Colitis, intestinal
disorders abdominal pain, constipation haemorrhage, perforation
severe nausea and paralyticus ileus,
vomiting intestinal obstruction,
pseudomembranose
colitis
Investigations Increase in Hypokalaemia,
transaminases hyponatremia
levels, increase in
alkaline
phosphatase,
increase of
bilirubin, increase
of creatinine
Blood and Neutropenia, Febrile neutropenia, Local reactions
lymphatic anaemia thrombocytopenia
disorders
Respiratory and Dyspnea Interstitial
thoracic disorders pneumonitis (if
combined)
Infections and Infections
infestations
Immunological Allergic reactions Anaphylactic
disorders reactions
Very rare (<1/10,000)
Increase in amylase and lipase
Autoimmune thrombocytopenia (if combined)
Speech disturbances (transient)

Irinotecan should be administered once all adverse effects are recovered to grade 0-1
according to NCI-CTC (National Cancer Institute Common Toxicity Criteria).
Treatment should be delayed for 1-2 weeks if patient needs to recover.
If neutropenia grade 4, febrile neutropenia grade 3-4 and fever grade 2-4,
thrombocytopenia grade 4 and leucopenia grade 4, irinotecan should be reduced by 15-20%.
It non-haematological toxicity grade 3-4 irinotecan should be reduced by 15-20%.
234 E. Una Cidon

CONCLUSION
Camptothecins are broad-spectrum anticancer drugs that specifically target DNA
topoisomerase I (Topo I) [1]. Irinotecan belongs to these drugs and its activity is due to rapid
formation of an in vivo active metabolite, SN-38 [3]. Preclinical studies suggest that the
drug's antitumor and toxic effects may be schedule-dependent. It has shown potent antitumor
activity against a wide range of tumors [2], but unfortunately, resistance to this drug is
common and several studies have been performed to show possible mechanisms and use
some biological modulation to resolve it. At least part of the interpatient variability of
irinotecan toxicity can be explained by the UGT1A1*28 polymorphism. When homozygous
for the UGT1A1*28 allele the risk of severe neutropenia is high, especially with the 300-350-
mg/m2 regimen. A molecular assay is now available to identify this subgroup and should be
used to guide irinotecan-treatment decisions.

REFERENCES
[1] Ramesh M, Ahlawat P, Srinivas NR. Irinotecan and its active metabolite, SN-38:
review of bioanalytical methods and recent update from clinical pharmacology
perspectives. Biomed. Chromatogr. 2010 Jan; 24(1): 104-23. doi: 10.1002/bmc.1345.
[2] Y. Xu and M. A. Villalona-Calero. Irinotecan: mechanisms of tumor resistance and
novel strategies.
[3] for modulating its activity. Annals of Oncology 13: 1841-1851, 2002
[4] Eckhardt SG. Irinotecan: a review of the initial phase I trials. Oncology (Williston
Park). 1998 Aug; 12(8 Suppl 6): 31-8.
[5] Irinotecan. http://www.aemps.gob.es/cima/pdfs/es/ft/70886/70886_ft.pdf (Spanish).
[6] Camptosar. http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/020571s026lbl.
pdf.
In: The Easy Book of Cancer Pharmacology ISBN: 978-1-63485-038-4
Editor: Esther Una Cidon © 2016 Nova Science Publishers, Inc.

Chapter 27

LAPATINIB

V. Reguero Cuervo1,, T. Sampedro Gimeno1


and P. García Teijido2
1
Hospital of Cabueñes, Gijón, Spain
2
Hospital San Agustín, Avilés, Spain

ABSTRACT
Human epidermal growth receptor 2 (HER2)- targeted therapies have revolutioned
the treatment of HER2-positive breast cancer, both in the metastatic and early stage.
Trastuzumab has been the cornerstone of anti-HER2 therapy. Despite overall promising
activity in HER2-positive breast cancer, patients develop primary or secondary resistance
to trastuzumab, prompting the development of alternative HER2 inhibitors. In contrast to
trastuzumab, who binds to the extracellular domain of HER2, Lapatinib is an inhibitor of
the intracellular tyrosine kinase domains of both EGFR (ErbB1) and of HER2 (ErbB2)
receptors which may overcome trastuzumab resistance. The use of Lapatinib is approved
for the treatment of adult patients with breast cancer, whose tumors overexpress HER2
(ErbB2). In this review, we focus on Lapatinib and examine its mechanism of action and
rationale for development, clinical efficacy in various settings, pharmacokinetics, dose
and regimen, safety and tolerability, and the current role in the management of metastatic
breast cancer.

Keywords: lapatinib, HER-2

INTRODUCTION
HER2 (ErbB2) was discovered in the mid-1980s and it is a member of the HER family of
transmembrane receptor tyrosine kinases, which also include ErbB1 (EGFR), ErbB3, and
ErbB4 [1-3]. Approximately 20% of breast cancers are characterized by gene amplification
and/or overexpression of HER2 [4]. These tumors historically represented an aggressive


virginia.reguero@sespa.es.
236 V. Reguero Cuervo, T. Sampedro Gimeno and P. García Teijido

subtype of breast cancer, but the prognosis has changed dramatically since the introduction of
anti-HER2 therapies, either for metastatic disease or locally advanced tumors [5, 6]. Despite
overall promising activity in HER2-positive breast cancer, half of the patients had progression
to trastuzumab plus chemotherapy by 7.4 months, indicating that de novo and acquired
resistance existed, and prompted the development of novel anti HER2 targeted agents [7].
Lapatinib, (Tyverb, GlaxoSmithKline, London, UK) is a small molecule that dually targets
the intracellular tyrosine kinase domains of both EGFR (ErbB1) and of HER2 (ErbB2)
receptors, allowing for complete blockage of the autophosphorilation reaction and a complete
halt to the downstream cascade of events [8-10].

CLINICAL PHARMACOLOGY
Drug Classification

Antineoplastic Agent, Anti-HER2; Antineoplastic Agent, Epidermal Growth Factor


Receptor (EGFR) Inhibitor; Antineoplastic Agent, Tyrosine Kinase Inhibitor.

MECHANISM OF ACTION
Lapatinib, a 4-anilinoquinazoline, is an inhibitor of the intracellular tyrosine kinase
domains of both EGFR (ErbB1) and of HER2 (ErbB2) receptors (estimated Kiapp values of
3nM and 13nM, respectively) with a slow off-rate from these receptors (half-life greater than
or equal to 300 minutes) [11-12]. Lapatinib reversibly binds to tyrosine kinase domains,
blocking phosphorylation and activation of downstream second messengers.
Lapatinib, following upstream HER2 signalling blockage, inhibits MAPK-Erk1/2 in
HER2 positive breast cancer cell lines, tumor xenografts, and in clinical tumor biopsies
obtained from women with HER2-positive breast cancer. Lapatinib, but not trastuzumab,
down-regulates survivin in HER2-positive breast cancer cell lines and in clinical tumors [13.]
Survivin down-regulation in Lapatinib-treated HER2 positive breast cancer cells is dependent
on PI3K inhibition and remains one of the most robust biological correlates of lapatinib
antitumor activity [13, 14].
Unlike other EGFR inhibitors like gefitinib and erlotinib, Lapatinib binds to an inactive-
like protein conformation. The combination with trastuzumab decreased HER2 ubiquitination
and increased the accumulation of inactive HER2 receptors at the cell surface and increased
antibody dependent cytotoxicity.
In summary, Lapatinib regulates cellular proliferation and survival in EGFR and HER2-
expressing tumors, inhibiting ErbB-driven tumor cell growth in vitro and in various animal
models and also in clinical tumors.
Lapatinib 237

PHARMACOKINETICS
Absortion The absolute bioavailability following oral administration of lapatinib is
unknown, but it is incomplete and variable (approximately 70% coefficient of
variation in AUC).
Serum concentrations appear after a median lag time of 0.25 hours (range 0 to
1.5 hours). Peak plasma concentrations (Cmax) of lapatinib are achieved
approximately 4 hours after administration.
Systemic exposure to lapatinib is increased when administered with food.
Distribution Lapatinib is highly bound (greater than 99%) to albumin and alpha-1 acid
glycoprotein. In vitro studies indicate that lapatinib is a substrate for the
transporters BCRP (ABCG1) and p-glycoprotein (ABCB1).
Lapatinib has also been shown in vitro to inhibit these efflux transporters, as
well as the hepatic uptake transporter OATP 1B1, at clinically relevant
concentrations (IC50 values were equal to 2.3 μg/ml).
The clinical significance of these effects on the pharmacokinetics of other
medicinal products or the pharmacological activity of other anti-cancer
medicinal products is not known.
Metabolism Lapatinib undergoes extensive metabolism, primarily by CYP3A4 and
CYP3A5.
Excretion The half-life of lapatinib measured after single doses increases with increasing
dose.
However, daily dosing of lapatinib results in achievement of steady state
within 6 to 7 days, indicating an effective half-life of 24 hours.
Lapatinib is predominantly eliminated through metabolism by CYP3A4/5.
Biliary excretion may also contribute to the elimination.
The primary route of excretion for lapatinib and its metabolites is in faeces.
Recovery of unchanged lapatinib in faeces accounts for a median 27% (range
3 to 67%) of an oral dose.
Less than 2% of the administered oral dose (as lapatinib and metabolites) is
excreted in urine.

Based on the population pharmacokinetic analysis, no significant difference was


observed in the pharmacokinetics of Lapatinib between patients <65 years and patients ≥65
years, but definitive evidence is lacking. No dedicated renal impairment trial for Lapatinib
has been conducted. Based on the results of the population pharmacokinetic analysis, dose
adjustment may not be necessary in patients with mild to moderate renal impairment. Due to
extensive hepatic metabolism, administration of lapatinib in patients with hepatic impairment
should be undertaken with caution and dose may be reduced.

MECHANISM OF RESISTANCE
In patients with HER2+ metastatic breast cancer, anti-HER2 therapies either as single-
agent or in combination with chemotherapy are effective, however a percentage of patients do
238 V. Reguero Cuervo, T. Sampedro Gimeno and P. García Teijido

not respond or develop resistance. The factors that confer resistance to Lapatinib are not well
characterized but may include modification of downstream effectors (for instance increased
levels of estrogen receptors and FoxoA3) and activation of alternative pathways (for instance,
failure to downregulate survivin, overexpression of AXL, overexpression of MCL-1,
overexpression of XIAP, upregulation of SRC family kinases, activation of RelA, up
regulation of betha1 integrin-mediated signaling, upregulation of Grb7, decreased
phosphorylation of eEF2, mutations in phosphatidylinositol 3-kinase catalytic subunit alpha
gene) [10, 13, 15-20]. Unlike trastuzumab, in which mutations in phosphatase and tensin
homologue deleted on chromosome 10 (PTEN), a phosphatase that dampens
phosphatidylinositol 3-kinase-Akt signaling predicts for poor prognosis, PTEN mutations
have not been shown to affect lapatinib efficacy [21].

Indications

Lapatinib is indicated for the treatment of adult patients with metastatic breast cancer,
whose tumors overexpress HER2.
It is indicated in combination with:
Capecitabine for patients with advanced or metastatic disease with progression following
prior therapy, which must have included anthracyclines and taxanes and therapy with
trastuzumab [22, 23].
Trastuzumab for patients with hormone receptor-negative metastatic disease that has
progressed on prior trastuzumab therapy(ies) in combination with chemotherapy (EGF104900
study) [24, 25].
Aromatase inhibitor for postmenopausal women with hormone receptor positive
metastatic disease, not currently intended for chemotherapy. The patients in the registration
study were not previously treated with trastuzumab or an aromatase inhibitor. No data are
available on the efficacy of this combination relative to trastuzumab in combination with an
aromatase inhibitor in this patient population [26].
There is no recommendation to specifically use Lapatinib in patients with brain
metastases [27-31].

Dosages

 Lapatinib/capecitabine combination posology

The recommended dose of Lapatinib is 1250 mg (i.e., five tablets) once daily
continuously.

 Lapatinib/trastuzumab combination posology:

The recommended dose of Lapatinib is 1000 mg (i.e., four tablets) once daily
continuously.
Lapatinib 239

 Lapatinib/aromatase inhibitor combination posology:

The recommended dose of Lapatinib is 1500 mg (i.e., six tablets) once daily
continuously.

METHODS OF PREPARATION/ADMINISTRATION
Lapatinib is provided as film-coated tablet (tablet). Lapatinib should be taken either at
least one hour before, or at least one hour after food. To minimize variability in the individual
patient, administration of Lapatinib should be standardized in relation to food intake, for
example always to be taken one hour before a meal. Dividing dose throughout the day is not
recommended.
Missed doses should not be replaced and the dosing should resume with the next
scheduled daily dose.

Note

For combination treatment with capecitabine, this one should be administered in two
doses, approximately 12 hours apart and taken with food or within 30 minutes after a meal.

SPECIAL INFORMATION AND CAUTIONS


Contraindications

Hypersensitivity to the active drug or to the excipients listed below:

 Tablet core
 Microcrystalline cellulose
 Povidone (K30)
 Sodium carboxymethyl starch (type A)
 Magnesium stearate
 Coated tablet
 Hypromellose
 Titanium dioxide (E171)
 Macrogol 400
 Polysorbate 80
 Yellow iron oxide (E172)
 Red iron oxide (E172)
240 V. Reguero Cuervo, T. Sampedro Gimeno and P. García Teijido

Elderly

No overall differences in safety or effectiveness were observed between elderly and


younger subjects.

Pediatric

Safety and efficacy has not been established.

Renal Impairment

Renal impairment is unlikely to affect the pharmacokinetics of this drug.

Hepatic Impairment

A dose reduction should be considered if hepatic severe impairment. Caution should be


applied when administering this drug to patients with moderate liver impairment.

Immunisations

Live vaccines should not be applied while taking the treatment or for at least 6 months
afterwards. Other vaccines can be administered, though may not give as much protection as
usual. In any case, it is safe to be in contact with other people who have had live vaccines as
injections. There can be problems with oral vaccines. Any contacts with someone who has
had oral polio, cholera or typhoid vaccination recently, should be avoided.

Pregnancy

It can cause fetal harm when administered to a pregnant woman. Women should be
advised not to become pregnant while taking lapatinib.

Breast-Feeding

It is not known whether lapatinib is excreted in human milk but nursing is not adviced
while on the treatment.
Lapatinib 241

WARNINGS
Left Ventricular Ejection Fraction (LVEF)

Reduction in LVEF have been reported. A normal LVEF before starting this drug needs
to be confirmed and to continue monitoring periodically [10, 22, 23, 24, 32].
LVEF decreases have been reported in approximately 1% of patients receiving Lapatinib
and were asymptomatic in more than 70% of cases.
LVEF decreases, resolved or improved in more than 70% of cases, in approximately 60%
of these on discontinuation of treatment with Lapatinib, and in approximately 40% of cases it
was continued.
Lapatinib has not been evaluated in patients with symptomatic cardiac failure.
Caution should be taken if Lapatinib is to be administered to patients with conditions that
could impaired LVEF (including co- administration with potentially cardiotoxic medicinal
products).
Symptomatic LVEF decreases were observed in approximately 0.3% of patients who
received Lapatinib monotherapy or in combination with other anti-cancer medicinal products.
LVEF decreases were reported in 2.5% of patients who received Lapatinib in
combination with capecitabine, as compared to 1.0% with capecitabine alone.
LVEF decreases were reported in 3.1% of patients who received Lapatinib in
combination with letrozole as compared to 1.3% of patients receiving letrozole plus placebo.
LVEF decreases were reported in 6.7% of patients who received Lapatinib in
combination with trastuzumab, as compared to 2.1% of patients who received Lapatinib alone
[10, 22, 24, 32].

Hepatotoxicity

Monitor liver tests before starting the treatment, continue monitoring during treatment
and as clinically indicated.
Stop it if severe raise in liver function tests and do not restart it.
Dose reduction in patients with severe hepatic impairment should be considered.

QT Interval Prolongation

The potential of Lapatinib to prolong the QTc interval has not been ruled out, but it has
only been observed in a dose-dependent manner in an uncontrolled phase I trial. ECG and
electrolytes monitoring should be performed.

Diarrhoea

It needs to be managed with anti-diarrheal drugs and replace fluids and electrolytes if
severe.
242 V. Reguero Cuervo, T. Sampedro Gimeno and P. García Teijido

Diarrhoea occurred in approximately 65% of patients who received lapatinib in


combination with capecitabine, in 64% of patients who received lapatinib in combination
with letrozole and in 62% of patients who received lapatinib in combination with
trastuzumab. Most cases of diarrhoea were grade 1 or 2 and did not result in discontinuation
of treatment with lapatinib.

Interstitial Lung Disease and Pneumonitis

Stop lapatinib if serious respiratory symptoms.

Rash

Rash occurred in approximately 28% of patients who received lapatinib in combination


with capecitabine, in 45% of patients who received lapatinib in combination with letrozole
and in 23% of patients who received lapatinib in combination with trastuzumab.
Rash was generally low grade and did not result in discontinuation of treatment with
lapatinib. Prescribing physicians are advised to perform a skin examination prior to treatment
and regularly during treatment.
Patients experiencing skin reactions should be encouraged to avoid exposure to sunlight
and apply broad spectrum sunscreens with a Sun Protection Factor (SPF) ≥30. If a skin
reaction occurs a full body examination should be performed at every visit until one month
after resolution. Patients with extensive or persistent skin reactions should be referred to a
dermatologist.

TOXICITIES
The following adverse reactions have been reported to have a causal association with
lapatinib alone or lapatinib in combination with capecitabine, trastuzumab or letrozole.

System organ Very Common Common Uncommon Rare


class ≥1/10 ≥1/1000 to <1/10 ≥1/1,000 to (≥1/10.000 a
<1/1000 <1/1.000)
Immune system Hypersensitivity
disorders reactions
including
anaphylaxis
Metabolism and Anorexia
nutrition
disorders
Psychiatric Insomnia*
disorders
Nervous system Headache† Headache*
disorders
Cardiac Decreased left ventricular
disorders ejection fraction
Lapatinib 243

System organ Very Common Common Uncommon Rare


class ≥1/10 ≥1/1000 to <1/10 ≥1/1,000 to (≥1/10.000 a
<1/1000 <1/1.000)
Respiratory, Epistaxis†, cough†, Interstitial
thoracic and dyspnoea† lung disease/
mediastinal pneumonitis.
disorders
Gastrointestinal Diarrhoea, which Constipation†
disorders may lead to
dehydration, nausea,
vomiting,
dyspepsia*,
stomatitis*,
constipation*,
abdominal pain*
Hepatobiliary Hyperbilirubinaemia,
disorders hepatotoxicity
Skin and Rash (including Nail disorders including
subcutaneous dermatitis paronychia
tissue disorders acneiform), dry
skin*†,
palmar-plantar
erythrodysaesthesia*,
alopecia†, pruritus†
Musculoskeletal Pain in extremity*†,
and connective back pain*†,
tissue disorders arthralgia†
General Fatigue, mucosal
disorders and inflammation*,
administration asthenia†
site conditions
Vascular Hot flush†
disorders
*These adverse reactions were observed when lapatinib was administered in combination with capecitabine. †These
adverse reactions were observed when lapatinib was administered in combination with letrozole.

DOSE MODIFICATION
Cardiac Events

Lapatinib should be discontinued in patients with a decreased LVEF that is mild to


moderate and in patients with an LVEF that drops below the institution‘s lower limit of
normal.
Lapatinib may be restarted at a reduced dose (1,000 mg/day) and in combination with
letrozole may be restarted at a reduced dose of 1,250 mg/day after a minimum of 2 weeks if
the LVEF recovers to normal and the patient is asymptomatic.

Hepatic Impairment

There are no clinical data with this dose adjustment in patients with severe hepatic
impairment. However, a dose reduction from 1,250 mg/day to 750 mg/day or from 1,500
244 V. Reguero Cuervo, T. Sampedro Gimeno and P. García Teijido

mg/day to 1,000 mg/day in patients with severe hepatic impairment is predicted to adjust the
area under the curve (AUC) to the normal range and could be considered.

≥Grade 2 NCI CTCAE toxicity

Discontinuation or interruption of dosing with Lapatinib may be considered and can be


restarted at a lower dose.

Interactions

The concomitant use of strong CYP3A4 inhibitors should be avoided due to risk of
increased exposure to lapatinib (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir,
indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole).
Grapefruit may also increase plasma concentrations of lapatinib and should be avoided.
The concomitant use of strong CYP3A4 inducers should be avoided due to risk of
decreased exposure to lapatinib (e.g., dexamethasone, phenytoin, carbamazepine, rifampin,
rifabutin, rifapentin, phenobarbital, St. John‘s Wort).
Co-administration of Lapatinib with orally administered medicinal products with narrow
therapeutic windows that are substrates of CYP3A4 and/or CYP2C8 should be avoided.
Concomitant treatment with substances that increase gastric pH should be avoided, as
lapatinib solubility and absorption may decrease.

CONCLUSION
HER2 targeted therapies have revolutionized the treatment of HER2-positive breast
cancer. Lapatinib was initially approved for patients with HER2-positive breast cancer whose
disease progressed under Trastuzumab-based treatments. Novel anti HER2 drug have been
recently added to our therapeutic armamentarium, but optimal sequence and combination is
unknown. However, some clear recommendations can be stated on Lapatinib. It is indicated
after failure of trastuzumab-based therapies in HER2 positive metastatic breast cancer
patients, and due to novel highly active and safe approved anti HER2, probably should only
be considered in third-line and beyond scenarios.
In the future, we could anticipate the routine use of genomic/proteomic approaches to
identify biomarkers and, based both in tumor and patient characteristics, select patients who
will optimally benefit from particular anti-HER2 agents or therapy combinations.

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Lapatinib 245

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vitro and in vivo. Mol Cancer Ther 2001, Dec;1(2):85-94.
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In: The Easy Book of Cancer Pharmacology ISBN: 978-1-63485-038-4
Editor: Esther Una Cidon © 2016 Nova Science Publishers, Inc.

Chapter 28

LENVATINIB, LENVIMA®

O. Martínez-Sáez, A. Madariaga-Urrutia, T. Alonso-Gordoa


and E. Grande-Pulido
Medical Oncology Department, Ramón y Cajal University Hospital, Madrid, Spain

ABSTRACT
Lenvatinib is an oral inhibitor of multiple receptor tyrosine kinases (RTKs) with
activity against vascular endothelial growth factor receptor (VEGFR1-3), fibroblast
growth factor receptor (FGFR1-4), platelet growth factor receptor (PDGFR), RET
(rearranged during transfection) and c-KIT. Lenvatinib modulates angiogenesis,
lymphangiogenesis and tumor proliferation through this network inhibition. The
difference between lenvatinib and other tyrosine kinase inhibitors (TKIs) with
antiangiogenic properties is based on the strong potency to inhibit FGFR-1 that is
involved in the mechanisms of resistance to VEGF/VEGFR inhibitors. Lenvatinib has
been recently approved by the Food and Drug Administration (FDA) and the European
Medicine Agency (EMA) for the treatment of patients with progressive, differentiated
thyroid cancer (DTC) refractory to radioactive iodine therapy. Lenvatinib showed a
significant improvement in progression free survival (PFS) compared with placebo
[median PFS of 18.3 months in lenvatinib group vs. 3.6 months with placebo (hazard
ratio 0.21; 99% CI, 0.14-0.31)] and also in response rates (almost 65% in the lenvatinib
group vs. 1.5% in the placebo assigned patients). Moreover, lenvatinib demonstrated
activity not only in those näive patients but also in patients who received prior treatment
with other multikinase inhbitors showing that levatinib is able to overcome resistance to
other antiangiogenic agents (HR 0.22 95%IC 012-0.41). The most common side effects
were hypertension, asthenia, diarrhea, anorexia, nausea, stomatitis and proteinuria. Other
adverse effects of special interest have also been described, as arterial and venous
thromboembolic effects and renal and hepatic failure. Although treatment related toxicity
of lenvatinib can be considered frequent and severe, most adverse events can be managed
with standard clinical interventions or dose modifications by expert physicians.


Enrique Grande Pulido; egrande@oncologiahrc.com.
250 O. Martínez-Sáez, A. Madariaga-Urrutia, T. Alonso-Gordoa et al.

Keywords: lenvatinib, TKIs, thyroid carcinoma

INTRODUCTION
Patients with advanced DTC that are refractory to 131 I treatment have a median life
expectancy of about 5 years and treatment options are limited in this setting [1, 2]. Signaling
network has been identified as important factor associated to tumor aggressiveness. Efforts
have been made to target angiogenesis and other molecular pathways of tumor growth [2].
Lenvantinib is an oral TKI that inhibits VEGFR 1 to 3 and other important growth pathways
as those mediated by FGFR and PDGFRα/β that has demonstrated significant improvements
in progression-free survival and the response rate among patients with iodine-131–refractory
thyroid cancer [2, 3].

CLINICAL PHARMACOLOGY
Drug Classification

Orally administrated, small molecule, and multiple RTKs inhibitor.

Mechanism of Action

Lenvatinib is an oral inhibitor of multiple RTKs targeting VEGFR1-3, FGFR1-4,


PDGFR, RET and KIT [3].
Lenvatinib modulates angiogenesis and lymphangiogenesis by inhibition of VEGFR,
FGFR, and PDGFRα/β. The difference between lenvatinib and other TKIs with
antiangiogenesis properties is based on its strong potency against FGFR-1 whose
upregulation has been suggested as a potential mechanism of resistance to VEGF/VEGFR
inhibitors in thyroid cancer cells. Lenvatinib has also a direct oncogenic effect in regulating
tumor cell proliferation by inhibiting RET, c-KIT, and PDGFRβ, and tumor microenviron-
ment development through FGFR and PDGFRβ inhibition [4-6].

Pharmacokinetics

Absorption Rapidly oral absorption [time to peak plasma concentration (tmax) range 1–4 h]
[5, 7, 8].
Distribution High volume of distribution (ranges from 50.5 to 336 L). High plasma protein
binding (97% to 98%) [7-9].
Metabolism Extensive liver and renal metabolism [7, 8, 10].
Excretion Excretion in urine and, more predominantly, in feces [7-9].
Lenvatinib, Lenvima® 251

Mechanism of Resistance

There is no proper mechanism of resistance currently described but all patients treated
with lenvatinib will eventually relapse. It is believed that upregulation of other pro-
angiogenic factors different that those targeted by lenvatinib might be responsible for this
resistance together with overexpression or activation of tumor surface tyrosine kinase
receptors or intracellular pathways.

Indications

Patients with advanced and progressive DTC, resistant to radioactive iodine.

Dosages

The recommended dose is 24 mg orally once daily. The maximum tolerated dose (MTD)
was established at 25 mg/day [5]. Dose reductions down to 20, 14 or 10mg qd are accepted
according to toxicity appearance.

Methods of Administration/Preparation

Lenvatinib is orally administered once daily at about the same time, without regard on the
timing of meals [9].

Special Information and Cautions

Contraindications
 Hypersensitivity to the active substance or to any of the excipients.
 Breast-feeding.

Elderly
No overall differences were seen in this population when compared to younger patients.

Pediatric
Safety and efficacy has not been established.

Renal Impairment
There are no data in patients with severe renal impairment (calculated creatinine
clearance ≤30 ml/min per the Cockcroft and Gault formula), or proteinuria greater than
1g/24h [2].
252 O. Martínez-Sáez, A. Madariaga-Urrutia, T. Alonso-Gordoa et al.

Hepatic Impairment
There are limited data in patients with hepatic impairment [2]. A study of
pharmacokinetic properties of lenvatinib was performed after a single dose of 10mg in
subjects with varying degrees of hepatic impairment and healthy volunteers. Results suggest
that subjects with severe hepatic impairment (Child-Pugh: 10–15) should start treatment at a
reduced dose of 14 mg [11].

Immunisations
Live vaccines should not be applied while taking the treatment or for at least 6 months
afterwards. Other vaccines can be administered, though may not give as much protection as
usual. In any case, it is safe to be in contact with other people who have had live vaccines as
injections. There can be problems with oral vaccines. Any contacts with someone who has
had oral polio, cholera or typhoid vaccination recently, should be avoided.

Pregnancy
There is no data on pregnancy. Females of childbearing potential and male subjects who
are partners of women of childbearing potential must use a highly effective method of
contraception [2].

Breast-Feeding
It is contraindicated.

Warnings

Thyroid Hormones
Serum thyrotropin levels should be measured on a regular basis, and the daily dose of
levothyroxine should be adjusted according to its serum levels [2].

Blood Pressure
Patients starting treatment with lenvatinib should have adequate blood pressure control
[2]. Blood pressure monitoring should be performed frequently.

Cardiac Impairment
There are no data from patients with significant cardiovascular impairment [2]. A healthy
volunteer single dose study with 32mg of lenvatinib did not show QTc prolongation at
clinically relevant high plasma levels [12].

Toxicity [2, 5]
Organic system Very Common Common ≥ 1/1000 to Uncommon Rare (≥ 1/10.000 a <
disorders ≥ 1/10 < 1/10 ≥ 1/1,000 to 1/1.000)
<1/1000
General disorders Fatigue
Decreased appetite
Decreased weight
Lenvatinib, Lenvima® 253

Organic system Very Common Common ≥ 1/1000 to Uncommon Rare (≥ 1/10.000 a <
disorders ≥ 1/10 < 1/10 ≥ 1/1,000 to 1/1.000)
<1/1000
Dysgeusia
ENT disorders Dysphonia
Nervous system Headache Posterior
disorders reversible
encephalopathy
syndrome
Blood and Neutropenia
lymphatic Thrombocytopenia
system disorders
Renal and urinary Proteinuria Renal failure
disorders
Gastrointestinal Diarrhea Nausea
disorders Stomatitis
Vomiting
Dyspepsia
Oropharyngeal pain,
Dry mouth
Upper abdominal
pain, Abdominal
pain, Constipation
Hepatobiliary Hepatic failure
disorders
Skin and Palmar–plantar
subcutaneous erythrodysesthesia
tissue syndrome, Rash
disorders Alopecia
Peripheral edema
Cardiovascular Hypertension Venous/arterial
disorders Thromboembolism
Investigations Hypocalcemia
Musculoskeletal Arthralgia
disorders Myalgia

Dose Modifications

In general, dose modifications are not recommended for common terminology criteria
adverse events (CTCAE) grade 1. Treatment should be temporarily discontinued if an
intolerable grade 2 and grade 3 or higher adverse event occurs. Once the adverse event has
resolved or improved to grade 1, lenvatinib should be restarted at one level dose reduction
(24, 20, 14 to a minimum of 10 mg per day). Once the dose has been reduced, increasing is
not permitted [2].

Hypertension
High BP and proteinuria have similar management to other VEGF and VEGFR
inhibitors. In subjects with both proteinuria and high blood pressure, treatment with
254 O. Martínez-Sáez, A. Madariaga-Urrutia, T. Alonso-Gordoa et al.

angiotensin-converting enzyme inhibitors or angiotensine II receptor antagonists are


preferred.
Lenvatinib should be stopped if there is risk of suffering an hypertensive crisis, or the
patient presents risk factors for potentially severe complications in relation with not
controlled hypertension (for example, BP ≥160/100mmHg, cardiac impairment risk factors,
intra-cranial hemorrhage). Once the patient has received within 48hours the same
antihypertensive treatment and BP is controlled, treatment with Lenvatimib should be
restarted.
If CTCAE grade 3 hypertension is developed, lenvatinib should be maintained if blood
pressure improves to baseline or grade 1 with anti-hypertensive medication [2]. Patients
without previous anti-hypertensive treatment should start a new drug, and those with a
previous treatment should increase the dosage, or add a new anti-hypertensive agent. If
systolic BP continues to be ≥160mmHg or diastolic ≥100mmHg, after the anti-hypertensive
treatment, lenvatinib should be stopped. Once BP is controlled for 48hours, lenvatinib should
be restarted with one dose level reduction. If dose reduction greater than 10mg per day is
required, lenvatinib should be stopped.
If CTCAE grade 4 hypertension is developed lenvatinib should be stopped, and
antihypertensive medication should be initiated.

Proteinuria
If urine testing strip is equal or greater than 2+, lenvatinib should be maintained and a 24
hours urine analysis should be performed within 72 hours. Proteinuria CTCAE grading will
depend on the 24 hours urine analysis. Dose modifications should be done according to
general specifications. After a second episode of proteinuria greater than 2+, subject should
perform a urine testing strip each 15 days until results are 1+ or negative during 3 months [2].

Interactions

There are no clinically relevant interactions in lenvatinib coadministration with substrates


of aldehyde oxidase or potent CYP3A4 and P-gp inducers [7, 11].

CONCLUSION
Lenvatinib is the second targeted agent approved by the FDA and EMA for differentiated
iodine-131–refractory thyroid cancer, showing an increase of more than five-fold the time to
disease progression in a placebo controlled trial [2, 13]. Treatment of related toxicity needs to
be considered when treating patients with lenvatinib to achieve an optimal dose and efficacy
during therapy. However, most adverse events, including hypertension and proteinuria, can be
managed with standard clinical interventions or dose modifications. Potentially fatal
thromboembolic and hemorrhagic events have been described [2].
Lenvatinib, Lenvima® 255

REFERENCES
[1] Schlumberger M, Brose M, Elisei R, et al. Definition and management of radioactive
iodine-refractory differentiated thyroid cancer. Lancet Diabetes Endocrinol. 2014;2:
356-8.
[2] Schlumberger M, Tahara M, Wirth LJ, et al. Lenvatinib versus placebo in radioiodine-
refractory thyroid cancer. N. Engl. J. Med. 2015; 12: 621-30.
[3] Yamamoto Y, Matsui J, Matsushima T, Obaishi H, Miyazaki K, et al. Lenvatinib, an
angiogenesis inhibitor targeting VEGFR/FGFR, shows broad antitumor activity in
human tumor xenograft models associated with microvessel density and pericyte
coverage. Vascular Cell. 2014;6.
[4] Stjepanovic N, Capdevila J. Multikinase inhibitors in the treatment of thyroid cancer:
specific role of lenvatinib. Biologics: Targets and Therapy. 2014;8:129–39.
[5] Boss DS, Glen H, Beijnen JH, Keesen M, Morrison R, Tait B, et al. A phase I study of
E7080, a multitargeted tyrosine kinase inhibitor, in patients with advanced solid
tumours. Brit. J. Cancer. 2012;106:1598–604.
[6] Glen H, Mason S, Patel H, Macleod K, Brunton VG. E7080, a multi-targeted tyrosine
kinase inhibitor suppresses tumor cell migration and invasion. BMC Cancer. 2011;11:
309.
[7] Shumaker RC, Aluri J, Fan J, Martinez G, Thompson GA, et al. Effect of Rifampicin on
the Pharmacokinetics of Lenvatinib in Healthy Adults. Clin. Drug Investig.
2014;34:651–9.
[8] Dubbelman AC, Rosing H, Nijenhuis C, Huitema ADR, Mergui-Roelvink M, et al.
Pharmacokinetics and excretion of 14C-lenvatinib in patients with advanced solid
tumors or lymphomas. Invest New Drugs. 2014.
[9] Yamada K, Yamamoto N, Yamada Y, Nokihara H, Fujiwara Y, et al. Phase I Dose-
Escalation Study and Biomarker Analysis of E7080 in Patients with Advanced Solid
Tumors. Clin. Cancer Res. 2011;17: 2528-37.
[10] Inoue K, Asai N, Mizuo H, Fukuda K, Kusano K, et al. Unique metabolic pathway of
[14C]lenvatinib after oral administration to male cynomolgus monkey. Drug Metab.
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[11] Inoue K, Mizuo H, Kawaguchi S, Fukuda K, Kusano K, et al. Oxidative metabolic
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2014;42:1326-33.
[12] Shumaker RC, Zhou M, Ren M, Fan J, Martinez G, Aluri J, et al. Effect of lenvatinib
(E7080) on the QTc interval: results from a thorough QT study in healthy volunteers.
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[13] Brose MS, Nutting CM, Jarzab B, et al. Sorafenib in radioactive iodine-refractory,
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blind, phase 3 trial. Lancet. 2014;384:319-28.
In: The Easy Book of Cancer Pharmacology ISBN: 978-1-63485-038-4
Editor: Esther Una Cidon © 2016 Nova Science Publishers, Inc.

Chapter 29

MITOMYCIN C
MITOMYCIN-C KYOWA [3], MUTAMYCIN, AMETYCINE,
MITOCIN-C, MITOLEM,
MITO-MEDAC [1] MITOSOL [12]

M. Uherek
University Hospital Southampton NHS Foundation Trust, Southampton, UK

ABSTRACT
Mitomycin C (MITO-C) [2] is an antitumour antibiotic derived from Streptomyces
caespitosus. It is active against a wide variety of malignancies [3] and as a topical agent
in treatment of glaucoma [12]. It is most commonly used concurrently with radiotherapy
in the treatment of bladder [9] and anal cancer [15, 16] and as intravesical chemotherapy
for non-muscle invasive bladder cancer [5, 11]. In other settings it has been largely
replaced by newer agents [21]. It has a distinct blue colour. Mitomycin acts as an
alkylating agent causing inhibition of DNA synthesis and function by inducing cross-
linking and as bioreductive agent resulting in free radical formation [18]. It also degrades
preformed DNA, causes lysis of the nucleus and formation of giant cells [19] and inhibits
transcription [18]. Mitomycin has maximum effect in late G- and early S-phases [19], and
it is preferentially activated in hypoxic tumour cells [18]. The most significant toxicity is
a delayed and cumulative myelosuppresson with a nadir of 5-6 weeks after administration
[4]. There are reports of severe pulmonary toxicity, which are increased by previous or
synchronous administration of vinca alkaloids [4]. It is a vesicant agent and great care
should be taken during intravenous (iv) administration to avoid extravasation [3].

Keywords: mitomycin C, mutamycin, MMC, MTC, MITC, MITO-C


Email: maja.uherek@googlemail.com.
258 M. Uherek

INTRODUCTION
Mitomycin C was first isolated from Streptomyces caespitosus in Japan in 1958, however
due to toxicity, its use was not immediately adopted. In 1974 delayed myelosupprosion was
recognized, which led to development of more rational treatment protocols [4]. Mitomycin
containes three anticancer groups - quinine, urethane and aziridine [23]. Mitomycin leads to
alkylation at the O-6 position of guanosine and has been shown to produce DNA cross-links
[4], which results in inhibition of DNA synthesis and function [18]. By targeting DNA-
dependent RNA polymerase mitomycin inhibits transcription. Mitomycin c is preferentially
activated in the hypoxic cells. Biological reductive activation by NADPH cytochrome p450
reductase, DT-diaphorase, NADH cytochrome B450 reductase results in oxygen free radical
formation, which contributes to the cutotoxic effect of mitomycin [18].

CLINICAL PHARMACOLOGY
Drug Classification

Pharmacokinetics

Absorption Oral Erratic absorption. High doses required to achieve adequate


peak plasma concentration leading to myelosuppression [4].
Intravesical Minimal absorption into the systemic circulation. [24]
Correlation with the extent of TURBT [5].
Intraocular Unknown
Intraperitoneal The ratio concentration of mitomycin in perfusate and in plasma
is reported to vary between 10 and 29 [13].
Distribution 22 L/m2 [6].
Rapidly cleared from plasma after intravenous administration [3].
Metabolism Metabolised by the liver cytochrome P450 and DT-diaphorase with formation of
active and inactive metabolites. Bioactivation can occur in the spleen, heart and
kidneys [18].
The rate of clearance is inversely proportional to the maximal serum concentration
because of saturation of the metabolic pathways [3].
Excretion Mainly hepatobiliary system [18].
Renal clearance 8-10% [3, 18].
Half-life 50 minutes [18].

MECHANISM OF RESISTANCE [18]


1. Increased expression of the multidrug-resistance gene leads to increased mitomycin
efflux and decreased intracellular accumulation of the drug
2. Decreased expression of DT-diaphorese leading to decreased bioactivation of
mitomycin
Mitomycin C Mitomycin-C Kyowa [3] … 259

3. DNA repair through the increased activity of the DNA excision repair enzymes
4. Increased expression of gluthatione

INDICATIONS
 Anal Cancer [15, 16]
 Bladder Cancer (intravesical and concurrently with radiotherapy) [5, 9, 22, 25]
 Gastric cancer [3, 19]
 Pancreatic cancer [3, 19]
 Breast cancer [3, 18, 19]
 Non small cell lung cancer [3, 18]
 Cervical cancer [3, 18, 19]
 Head and neck cancer [18, 19]
 Pseudomyxoma peritonei [14]

DOSAGES
Chemoradiotherapy with mitomycin C and 5-fluorouracil for squamous cell carcinoma of
the anus and transitional cell carcinoma of the bladder:
Mitomycin C 10-12mg/m2 (maximum 20mg) intravenous (iv) day 1 of week 1 only.
Infuse as slow iv push or slow infusion in normal saline over 15-30 minutes. 5-fluorouracil
1000mg/m2 IV on day 1-4 and and 29-32 [8, 9, 10].
Non-muscle invasive bladder cancer intravesical instillation:
Post-operative dose of mitomycin C: 40mg in 40ml of water - once only [11].
Course: 40mg in 40ml of water at weekly intervals [11] for up to 3 years [22, 24].
Breast and gastric cancer:
10mg/m2 IV every 8 weeks as part of the combination regimens [18].

METHODS OF PREPARATION/ADMINISTRATION
Mitomycin C 0.2mg [11] 2mg, 10mg, 20mg and 40 mg.
Powder for solution for injection [3].
Blue-purple crystalline powder [3].

IV

The contents of the vial should be reconstituted with water for injection or saline 5 ml for
the 2 mg vial, 10 ml for the 10 mg vial, 20 ml for the 20 mg. If possible, avoid mixing with
injectable solutions which have a low pH [3].
IV the dose should be given slowly in order to avoid extravasation [3].
260 M. Uherek

Intravesical

After instillation of mitomycin into the urinary bladder, the urinary catheter should be
clamped for 1 hour. During this period patient should be rotated every 15 minutes to ensure
that the whole bladder urothelium comes to contact with the drug. Care must be taken to
avoid contamination of the inguinal area and genitalia [3].

Intraocular

Reconsitute 0.2mg vial of mitomycin add 1ml of sterile water for injection and saturate
the sponges [12].

Intraperitoneal

Subject of ongoing research. Dosage and method of administration vary.

Intra-Arterial

Mitomycin C can be given by the intra-arterial route directly into the tumours [3].

SPECIAL INFORMATION AND CAUTIONS


Contraindications

 Hypersensitivity to the active drug or the excipient.


 If thrombocytopenia or coagulation disorders.

Elderly Patients

Special consideration should be taken in treatment of elderly patients, as bone marrow


depression and renal disorders are more likely to occur due to reduced physiological function
[3].

Pediatric Patients

Use is not recommended in children.


Mitomycin C Mitomycin-C Kyowa [3] … 261

Renal Impairment

Caution in renal insufficiency. See dose modifications.

Hepatic Impairment

Use is not recommended in hepatic insufficiency.

WARNINGS
Extravasation

Ulceration and cellulitis may occur after extravasation during iv injection. Skin
induration and necrosis may be caused by the extravascular leakage [3]. If extravasation
occurs withdraw fluid, apply ice pack to the affected site and follow the local protocol. In
extreme cases involve plastic surgeon [18].

Skin Contact

Mitomycin should not come to contact with the skin. If skin contamination occurs, it
should be washed several times with 8.4% sodium bicarbonate, followed by soap and water
[3].

Use of Creams

Hand creams should not be used before mitomycin preparation and administration as they
may assist the penetration of the drug into the epidermal tissue [3].

With Radiotherapy and Other Antineoplastic Agents

Mitomycin should be administered with care in patients receiving radiotherapy or other


antineoplastic drugs. Full blood count, renal and liver function tests should be regularly
performed during treatment.

Intraarterial Injection

This may cause skin disorders such as pain, redness, erythema, blisters, erosion and
ulceration which may lead to skin/muscle necrosis.
262 M. Uherek

Injection into the hepatic artery may cause haemorrhage, perforation, gastroduodenal
ulcer. Administration should be promptly discontinued if any of these symptoms occur [3].

Use of Oxygen

Oxygen should be used only to maintain adequate saturation, as cases of acute distress
syndrome (ARDS) have been reported in patients received combination chemotheray with
mitomycin and high-flow oxygen [18, 19].

INTERACTIONS
Vinca alkaloids - can cause shortness of breath and bronchospasm if given
simultaneously or if administered previously [17].
Anthracyclines - increased incidence of cardiomyopathy [17].
Tamoxifen - increased risk of haemolytic uraemic syndrome [9].
Aldesleukin - skin reactions, stomatitis, alopecia, injection site cellultis and necrosis [2].

TOXICITIES [3, 19]


Organic Very common Common Uncommon Rare
disorders ≥1/10 ≥1/100 and <1/10 ≥1/1000 and ≥1/10,000 and
<1/100 <1/1000
Hair, nails and Nail Dermatitis, rash, palmar- Alopecia Widespread rash
skin disorders banding/discolouration plantar erythema
Cellulitis, induration and
soft tissue necrosis after
extravasation
Vascular Hypertension
disorders
Cardiac Congestive heart
disorders failure

General Anorexia Fatigue, fever


disorders
Neurological Paresthesia Neurologic
disorders abnormalities
(usually after doses
>50mg/m2 [18])
Gastrointestinal Nausea and vomiting Diarrhoea,
disorders occurs usually after 1-2 mucositis,
hours and may persist for stomatitis
2-3days
Blood and Anaemia, leukopenia
lymphatic severe within 8 weeks,
disorders thrombocytopenia within
8 weeks, apparent
Mitomycin C Mitomycin-C Kyowa [3] … 263

recovery may be
followed by depression
Organic Very common Common Uncommon Rare
disorders ≥1/10 ≥1/100 and <1/10 ≥1/1000 and ≥1/10,000 and
<1/100 <1/1000
Renal and Local irritation Kidney impairment - Renal failure,
bladder (intravesical instillation) elevated blood urea microangiopathic-
disorders cystitis, heamaturia, nitrogen and/or haemolytic
increased frequency of creatinine. Risk increases anaemia (MAHA
micturition, dysuria, significantly with doses syndrome),
nocturia >50mg/m2 haemolytic
uraemic syndrome
(HUS)
Hepatobiliary Liver disease,
disorders transaminitis,
jaundice,
hepatic veno-
occlusive disease
(abdominal pain,
hepatomegaly,
liver failure)
Respiratory and Cough, dyspnoea, Pulmonary
thoracic pneumonitis, interstitial hypertension,
disorders pneumonia pulmonary veno-
occlusive disease
(PVOD),
pulmonary oedema
Infections and Life-threatening
infestations infection, sepsis
Very rare (1 in 10000)
Anaphylaxis
Unknown
Ulceration after intravesical administration
Hypoglycemia
Adult respiratory distress syndrome

DOSE MODIFICATIONS
Dosage in Renal Impairment [26]

CrCL (ml/min) Dose


>60 100%
10-60 75%
<10 50%

Dosage in Hepatic Impairment [27]

No information found. Clinical decision when AST > 2x upper level normal (ULN).
264 M. Uherek

CONCLUSION
Although the use of mitomycin carries a risk of potentially serious toxicity, its efficacy
has been confirmed by multiple randomised clinical trials. The Anal Cancer Trial Working
Party of the United Kingdom Coordination Committee on Cancer Research (UKCCCR)
randomised 585 patients with T1-T4 suqamous cell carcinoma of the anus between two
different radiotherapy schedules and radiotherapy with concurrent mitomycin C and 5-
fluorouracil. Addition of chemotherapy was associated with reductions of local failure 61%
versus (vs) 39% and disease-related mortality 28% vs 39%.
Another trial conducted by the European Organization for the Research and treatment of
Cancer (EORTC) randomised patients with T3-4 or N-1-3 anal cancer between radiotherapy
alone or with addition of mitomycin C and 5-fluorouracil. Significantly higher complete
pathologic response rates were achieved in the chemoradiation arm 80% vs 54%, 32% higher
colostomy-free rate and 18% higher 5-year regional control rate.
Role of mitomycin in the treatment of anal cancer was questioned as it causes significant
toxicity. This subject was addressed by the trial from the Radiation Therapy Oncology Group
(RTOG) and the Easter Cooperative Oncology Group (ECOG). In this trial 310 patients were
randomly assigned to chemoradiotherapy with or without mitomycin C. Patients in the
mitomycin arm had significantly better disease-free survival 73% vs 51% and colostomy-free
survival 71% vs 59%. Overall survival and pathologic complete response rates were similar.
Grade 4 toxicity and fatal neutropenic sepsis were higher in mitomycin group [16].
Cancer Research UK Group conducted a multicentre phase III randomised trial between
August 2001 and April 2008 to establish the effect of neoadjuvant and concurrent
chemoradiotherapy on the locoregional disease-free survival in patients with muscle-invasive
bladder cancer. 360 patients were allocated to neoadjuvant chemotherapy, chemoradiotherapy
with mitomycin C and 5-fluorouracil or radiotherapy alone and/or to standard radiotherapy vs
reduced high-dose volume RT to tumor. Two-year event-free rates were 71% in the
chemoradiotherapy group and 58% in the radiotherapy only group. Two year survival was
was 63% and 58% respectively [25].
Intravesical treatment with mitomycin has a clear role in the treatment on non-muscle
invasive bladder cancer. In 2007 meta-analysis a single dose of mitomycin administered post-
operatively resulted in 17% average absolute reduction in early tumour recurrence [22].
Mitomycin also showed benefit in extended maintenence therapy in patients with non-
muscle-invasive bladder cancer. In a multicentre trial, 495 patients were randomised to
intravesical treatment with weekly BCG for six weeks, mitomycin 20mg weekly for six
weeks or mitomycin 20mg weekly weekly for six weeks and then monthly for 36 months.
Three-year recurrence-free rates for these arms were 66%, 69% and 86% respectively [24].

REFERENCES
[1] National Cancer Institute Drug Dictionary Mitomycin C.
[2] Litt's Pocketbook of Drug Eruptions and Interactions, Third Edition p. 367.
[3] Medicines and Healthcare products Regultory Agency. Mitomycin C - summary of
product characteristics and patient information leaflet. Accessed July 2015.
Mitomycin C Mitomycin-C Kyowa [3] … 265

[4] Stanley T. Crooke Archie W. Prestayko. Cancer and chemotheray Vol. III.
Antineoplastic Agents (1981) Academic Press.. p. 49-59.
[5] Maffezzini M1, Campodonico F, Manuputty EE, Puntoni M, Martelli A, Marini V,
Tamagno S, Mattioli F. Systemic Absorption and Pharmacokinetics of Single-dose
Early Intravesical Mitomycin C After Transurethral Resection of Non-muscle-invasive
Bladder Cancer. Urology. 2013 Aug;82(2):400-4. doi: 10.1016/j.urology.2013.03.036.
Epub 2013 Jun 20.
[6] 4. Rose BD editor. Mitomycin. UpToDate 15.2 ed. Waltham, Massachusetts:
UpToDate®; 2007.
[7] McEvoy GK, editor. AHFS 2007 Drug Information. Bethesda, Maryland: American
Society of Health-System Pharmacists, Inc. p. 1139-.
[8] Clinical protocol South East London Cancer Network. Mitomycin C and 5-fluorouracil
with concurrent chemotherapy February 2008. Available online.
[9] Clinical Protocol for radical treatment of transitional cell cancer of the bladder. Avon,
Somerset and Wiltshire NHS Cencer Services. Available online.
[10] Mitomycin injection, United States Prescribing Information. US National Library of
Medicine. 2015.
[11] Clinical Protocol. Administration if Intravesical Mitomycin. Southampton University
Hospitals NHS Trust. Accessed July 2015.
[12] Mitosol (mitomycin) prescribing infromation. St. Louis. MO: Mobious Therapeutics.
[13] S. van Ruth, V. J. Verwaai, F. A. N. Zoetmulder. Surgical Oncology Clinics of North
America Management of Peritoneal Surface Malignancy 2003. Chapter six.
Pharmacokinetics of intraperitoneal mitomycin C.
[14] Angelo DrGiorgio, Enrico Pinto. Treatment of peritoneal surface malignancies. State of
the Art and Perspectives. Spriger 2015 p. 117.
[15] Northover J, Glynne-Jones R, Sebag-Montefiore D, et al. Chemoradiation for the
treatment of epidermoid anal cancer. 13-year follow-up of the first randomised
UKCCCR Anal Cancer Trial (ACT I). Br J Cancer 2010; 102:1123.
[16] Bartelik H, Roelofsen F, Eschwege F, et al. Concomitant radiotherapy and chemoterapy
is superior to radiotherapy alone in the treatment of locally advanced anal cancer:
results of a phase III randomized trial of the European Organization for Research and
Treatment of Cancer Radiotherapy and Gastrointestinal Cooperative Groups. J Clin
Oncol 1997; 15:2040.
[17] Flam M, John M, Pajak TF, et al. Role of mitomycin in combination with fluorouracil
and radiotherapy, and salvage chemoradiation in the definitive nonsurgical treatment of
epidermoid carcinoma of the anal canal: results of phase III randomized intergroup
study. J Clin Oncol 1996; 14:2527.
[18] Casciato, D. Manual of Clinical Oncology 7th edition p. 85.
[19] Edward Chu, Vincent T. De Vita. Physicians' Cancer Chemotherapy Drug Manual
2013. London: Jones and Bartlett.
[20] BC Cancer Agency. Cancer Drug Manual. Mitomycin C. Revised 1 January 2015.
[21] BC Cancer Agency. (SCNAUSEA) Guidelines for Prevention and Treatment of
Chemotherapy-induced Nausea and Vomiting in Adults. Vancouver, British Columbia:
BC Cancer Agency; 1 November 2005.
[22] Edward D. Chan, Talmadge E. King Mitomycin-C pulmonary toxicity. UpToDate®.
Updated June 2015, accessed July 2015.
266 M. Uherek

[23] Hall MC, Chang SS, Dalbagni G, et al. Guideline for the management of nonmuscle
invasive bladder cancer (stages Ta, T1 and Tis): 2007 update. J Urol 2007; 178:2314.
[24] Mitomycin C - product information Sigma Aldrich. Available online.
[25] Thrasher JB, Crawford ED. Complications of intravesical chemotherapy. Urol Clin
North Am 1992; 19:529.
[26] James ND, Hussain SA, Hall E, Jenkins P, Tremlett J, Rawlings C et al. Results of a
phase III randomized trial of synchronous chemoradiotherapy compared to radiotherapy
alone in muscle invasive bladder cancer. J Clin Oncol 2010 28:15s, abstr 4517.
[27] Daniels S. North London Cancer Network, Dose adjustement for cytotoxics in renal
impairement. January 2009. Accessed 04/07/2015. Available online.
[28] Daniels S. North London Cancer Network, Dose adjustement for cytotoxics in hepatic
impairement. January 2009. Accessed 04/07/2015. Available online.
In: The Easy Book of Cancer Pharmacology ISBN: 978-1-63485-038-4
Editor: Esther Una Cidon © 2016 Nova Science Publishers, Inc.

Chapter 30

NINDETANIB. VARGATEF®

E. Una Cidon
Medical Oncology Department, Royal Bournemouth Hospital NHS Foundation Trust,
Bournemouth, UK

ABSTRACT

Nintedanib is a triple angiokinase inhibitor which binds competitively to the binding


site of adenosine triphosphate (ATP) and blocks intracellular signaling. This is crucial for
the proliferation and survival of endothelial and perivascular cells. When added to
docetaxel, it has demonstrated over one year (12.6 months) median overall survival for
advanced lung cancer patients with adenocarcinoma after first-line chemotherapy (vs.
10.3 months for patients receiving docetaxel alone). The approval of nintedanib is
primarily based on the positive results of the LUME-Lung 1 study of over 1,300 patients
[1, 2].

Keywords: nindetanib, angiokinase inhibitor

INTRODUCTION
Nintedanib is a triple angiokinase inhibitor which simultaneously inhibits vascular
endothelial growth factor receptors (VEGFR 1-3), platelet-derived growth factor receptors
(PDGFR α and ß) and fibroblast growth factor receptors (FGFR 1-3) signalling pathways. It
binds competitively to the binding site of adenosine triphosphate (ATP) of these receptors and
blocks intracellular signaling. Moreover, protein tyrosine kinase 3 Fms-like (Flt), the specific
protein tyrosine kinase lymphocytes (Lck) and protein tyrosine kinase Src proto-oncogene
(Src) are inhibited [1, 2].
When added to docetaxel, it has demonstrated over one year (12.6 months) median
overall survival for advanced lung cancer patients with adenocarcinoma after first-line
chemotherapy (vs. 10.3 months for patients receiving docetaxel alone). The approval of

Esther Una Cidon, aunacid@hotmail.com, Esther.unacidon@rbch.nhs.uk.
268 E. Una Cidon

nintedanib is primarily based on the positive results of the LUME-Lung 1 study of over 1,300
patients [1, 2].

CLINICAL PHARMACOLOGY
Drug Classification [1, 2]

Targeted therapy, angiokinase inhibitor.

Mechanism of Action [1, 2]


Nintedanib is a triple angiokinase inhibitor which simultaneously inhibits vascular
endothelial growth factor receptors (VEGFR 1-3), platelet-derived growth factor receptors
(PDGFR α and ß) and fibroblast growth factor receptors (FGFR 1-3) signalling pathways.
Nintedanib binds competitively to the binding site of adenosine triphosphate (ATP) of these
receptors and blocks intracellular signaling, which is crucial for the proliferation and survival
endothelial and perivascular (pericytes and vascular smooth muscle cells) cells. In addition
protein tyrosine kinase 3 Fms-like (Flt) are inhibited, the specific protein tyrosine kinase
lymphocytes (Lck) and protein tyrosine kinase Src proto-oncogene (Src).

Pharmacokinetics [3]
Absorption Bioavailability 4.7%
Undergoes substantial first-pass metabolism
Peak plasma concentration in 2-4 hours. Range 0.5-8 hours.
Steady plasma concentration in one week
Food increases systemic exposure by 20% and delays peak level to 4 hours
Distribution Protein bound is 97.8%, mainly albumin
Volume of distribution is 1050 L
Metabolism Hydrolytic cleavage by esterases resulting in the free acid moiety BIBF 1202 (25%)
BIBF 1202 is subsequently glucuronidated by UGT enzymes (UGT 1A1, UGT 1A7, UGT
1A8, and UGT 1A10) to BIBF 1202 glucuronide
CYP pathways (5%) mainly CYP3A4
Excretion 93.4% faeces/biliary
0.65% urine

MECHANISM OF RESISTANCE
Limited Data

Indications [1, 3]
Vargatef® in combination with docetaxel is indicated for use in adult patients with
locally advanced, metastatic or locally recurrent non-small cell lung cancer (NSCLC) of
adenocarcinoma histology, after first-line chemotherapy.
Nindetanib. Vargatef® 269

Dosages [3]

Recommended dosage is 200 mg twice daily between day 2 to 21 with docetaxel every
three weeks.

METHODS OF ADMINISTRATION/PREPARATION [3]


Take with food. Swallow capsule whole with liquid; do not chew or crush (bitter taste);
effect of crushing on the pharmacokinetics is unknown.
Capsules of 100 mg.

Special Information and Cautions [3]

Contraindications
 Hypersensitivity to the active drug, peanut, soya or any of the excipients listed
below:

Capsule content
Medium chain triglycerides
Hard fat
Lecithin (Soya) (E322)
Outer shell of the capsule
Gelatin
Glycerol (85%)
Titanium dioxide (E171)
Red iron oxide (E172)
Yellow iron oxide (E172)
Printing ink
Shellac
Black iron oxide (E172)
Propylene glycol (E1520)

Elderly
No dose adjustment is needed.

Pediatric
No data in children.

Renal Impairment
Mild-to-moderate: No dosage adjustment required
Severe (Creatinine Clearance <30 mL/min): Not studied
270 E. Una Cidon

Hepatic Impairment
Mild (Child Pugh A): No initial dose adjustment is needed.
Moderate-to-severe (Child Pugh B or C): Not recommended as not studied.

Immunisations
Live vaccines should not be applied while taking the treatment or for at least 6 months
afterwards. Other vaccines can be administered, though may not give as much protection as
usual. In any case, it is safe to be in contact with other people who have had live vaccines as
injections. There can be problems with oral vaccines. Any contacts with someone who has
had oral polio, cholera or typhoid vaccination recently, should be avoided.

Pregnancy
Females of childbearing potential must use a highly effective method of contraception as
it can cause fetal harm. The use of adequate contraception should be prolonged for at least 3
months after the last dose.

Breast-Feeding
Not known if it is excreted in women milk. Therefore nursing is contraindicated while on
the drug.

Warnings [3]

Liver Tests
Before initiating, monthly for 3 months, and then q3months thereafter and as clinically
indicated.

Gastrointestinal Symptoms
Diarrhea, nausea, and/or vomiting may occur. Treat accordingly and consider dose
modifications if needed or interruption.

Arterial Thromboembolic Events


Myocardial infarction may occur. Caution if high cardiovascular risk.

Bleeding and Gastrointestinal Perforation


Monitor for bleeding if on full anticoagulant therapy and adjust anticoagulation treatment
as needed.

Dose Modifications [3]

Diarrhoea, Nausea, and/or Vomiting


Temporarily interrupt treatment if symptoms persist despite hydration or
antidiarrheal/antiemetic medication. If unable to resume at full dose, decrease dose to 150 mg
per oral twice daily, which subsequently may be increased to the full dosage.
Nindetanib. Vargatef® 271

If a second reduction needs to be performed, reduce to 100 mg twice daily.


If patient does not tolerate 100 mg twice daily, stop treatment.

Toxicity [3]
Organic system Very Common Common ≥ 1/1000 to < 1/10 Uncommon
disorders ≥ 1/10 ≥ 1/1,000 to <1/1000
Infection disorders Febrile neutropenia, abscesses,
sepsis
Nervous system Peripheral neuropathy
disorders
Nutritional disorders Anorexia, electrolyte Dehydration
imbalance
Gastrointestinal Diarrhoea, nauseas, Perforation
disorders vomiting, abdominal pain
Hepatobiliary disorders Elevation AST, ALT, Hyperbilirubinemia
alkaline phosphatase
Skin and Mucositis, cutaneous
subcutaneous tissue eruption
disorders
Cardiovascular disorders Haemorrhage Hypertension,
thromboembolic events

Elevated Liver Enzymes


AST/ALT and bilirubin Dosage
AST/ALT >2.5xUNL and bilirubin > or 1.5xUNL Interrupt treatment until grade less 1
Reduce dose to 150 mg twice daily
AST and/or ALT >5xUNL If second reduction needed, 100 mg twice daily
AST and/or ALT >3xUNL and bilirubin >2UNL and If no clear cause for this, nindetanib should be
alkaline phosphatase <2 stopped permanently

Interactions [3]

Few chances of significant interactions as low biotransformation by CYP.


Smoking associated with decreased systemic exposure.

CONCLUSION
Nintedanib is a triple angiokinase inhibitor which simultaneously inhibits vascular
endothelial growth factor receptors (VEGFR 1-3), platelet-derived growth factor receptors
(PDGFR α and ß) and fibroblast growth factor receptors (FGFR 1-3) signalling pathways. It
binds competitively to the binding site of adenosine triphosphate (ATP) of these receptors and
blocks intracellular signaling. Moreover, protein tyrosine kinase 3 Fms-like (Flt), the specific
protein tyrosine kinase lymphocytes (Lck) and protein tyrosine kinase Src proto-oncogene
(Src) are inhibited [1, 2].
272 E. Una Cidon

When added to docetaxel, it has demonstrated over one year (12.6 months) median
overall survival for advanced lung cancer patients with adenocarcinoma after first-line
chemotherapy (vs. 10.3 months for patients receiving docetaxel alone). The approval of
nintedanib is primarily based on the positive results of the LUME-Lung 1 study of over 1,300
patients [1].
Nintedanib showed a manageable adverse event profile and it did not significantly
increase discontinuation rates, compared to docetaxel alone [1].

REFERENCES
[1] Reck M, Kaiser R, Mellemgaard A, et al. Docetaxel plus nintedanib versus docetaxel
plus placebo in patients with previously treated non-small cell lung cancer (LUME-
Lung 1): a phase 3, double-blind, randomised controlled trial. Lancet Oncol. 2014;15:
143–55.
[2] Hilberg F, Roth GJ, Krssak M, et al. BIBF1120: triple angiokinase inhibitor with
sustained receptor blockade and good anti-tumor efficacy. Cancer Res. 2008;68: 4774-
82.
[3] Vargatef, INN-Nintedanib - Europa. http://www.ema.europa.eu/docs/es_ES/document_
library/EPAR_-_Product_Information/human 002569/WC500179970.pdf.
In: The Easy Book of Cancer Pharmacology ISBN: 978-1-63485-038-4
Editor: Esther Una Cidon © 2016 Nova Science Publishers, Inc.

Chapter 31

NIVOLUMAB. OPDIVO®

E. Una Cidon
Medical Oncology Department, Royal Bournemouth Hospital NHS Foundation Trust,
Bournemouth, UK

ABSTRACT
Nivolumab is a human monoclonal antibody that blocks the interaction between PD-
1 and its ligands, PD-L1 and PD-L2. It has shown promising activity and safety in
melanoma when used as monotherapy but the efficacy may be even higher when used in
combination with ipilimumab. Among patients with advanced, previously treated
squamous-cell non-small cell lung carcinoma (NSCLC) and nonsquamous, overall
survival, was significantly better with nivolumab than with docetaxel, regardless of PD-
L1 expression leveln [1-3].
In patients with previously treated advanced renal-cell carcinoma, overall survival
was longer and fewer grade 3 or 4 adverse events occurred with nivolumab than with
everolimus [4].
Overall, the toxicity profile with this drug is manageable. Ongoing trials are
investigating its potential role alone or in combination with other therapies in multiple
cancer settings [1-4].

Keywords: nivolumab, human monoclonal antibody, PD-1, PD-L1, PD-L2

INTRODUCTION
Nivolumab is a human monoclonal antibody that blocks the interaction between PD-1
and its ligands, PD-L1 and PD-L2. The drug is administered intravenously (iv). In phase I/II
studies it has shown promising activity and safety and ongoing phase III trials are comparing
nivolumab with other standard of care therapies (chemotherapy, ipilimumab) for melanoma.


Email: aunacid@hotmail.com; Esther.unacidon@rbch.nhs.uk.
274 E. Una Cidon

The efficacy may be even higher when used in combination with ipilimumab (although the
toxicity will increase) [1].
Among patients with advanced, previously treated squamous-cell non-small cell lung
carcinoma (NSCLC), overall survival, response rate, and progression-free survival were
significantly better with nivolumab than with docetaxel, regardless of PD-L1 expression
level. Among patients with advanced nonsquamous NSCLC that had progressed during or
after platinum-based chemotherapy, overall survival was longer with nivolumab than with
docetaxel [2, 3].
In contrast to typical short-lived responses with cancer therapy in metastatic solid
tumours, many responses induced by nivolumab appear durable. Moreover, nivolumab has
got an acceptable tolerability profile [1-4].
Among patients with previously treated advanced renal-cell carcinoma, overall survival
was longer and fewer grade 3 or 4 adverse events occurred with nivolumab than with
everolimus [4].

CLINICAL PHARMACOLOGY
Drug Type

Carboxylic acids and derivatives. It is a targeted therapy, a human immunoglobulin G4


(IgG4) monoclonal antibody [5-7].

Mechanism of Action [5-7]

Nivolumab binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2,
releasing PD-1 pathway-mediated inhibition of the immune response, including the anti-
tumor immune response.

Pharmacokinetics [5-7]

Absorption Time to steady state 12 weeks


Route of administration is iv
Bioavailability is expected to be 100%
Distribution Volume of distribution 8 L
Metabolism Proteolytic degradation to small peptides and individual amino acids
and receptor-mediated clearance
Excretion Half-life 26.7 days
Clearance 9.5 mL/hr
Renal clearance is negligible
Nivolumab. Opdivo® 275

Indications [5-7]

Melanoma
Unresectable or metastatic melanoma after disease progression following ipilimumab
and, if BRAF V600 mutation positive, a BRAF inhibitor.

Non-small cell lung cancer (NSCLC)


Metastatic NSCLC with progression on or after platinum-based chemotherapy.
Patients with EGFR or ALK genomic tumor aberrations should have disease progression
on FDA-approved therapy for these aberrations prior to receiving nivolumab

Renal cell carcinoma


After anti-angiogenic therapy.

Dosage [5-7]

3 mg/kg as an intravenous (iv) infusion over 60 minutes every 2 weeks.

Methods of Preparation/Administration [5-7]

Only iv infusion over a period of 60 minutes. Do not administer as a bolus. Nivolumab is


a clear to opalescent, colorless to pale-yellow solution.
It comes in injection 40mg/4ml and 100mg/10ml solution in a single use vial.
Do not shake the vial. Withdraw the required volume of nivolumab and transfer it into an
iv container. Dilute it with 0.9% Sodium Chloride Injection or 5% Dextrose to prepare the
infusion with a concentration ranging from 1 to 10 mg/mL.
The product has not got a preservative, thus after preparation it should be stored at room
temperature for no more than 4 hours or under refrigeration at 2°C to 8°C for no more than 24
hours. Do not freeze.
It should be administered through an iv line containing a sterile, non-pyrogenic, low
protein binding in-line filter (pore size of 0.2 micrometer to 1.2 micrometer). Flush the iv line
at end of infusion.

Special Informations and Cautions [5-7]

Contraindications
-Hypersensitivity to the active drug or to its excipients listed below:
Sodium chloride Sodium citrate dihydrate
Mannitol (E421)
Pentetic acid (diethylenetriamine pentaacetic acid)
Polysorbate 80
Sodium hydroxide (for pH adjustment)
276 E. Una Cidon

Hydrochloric acid (pH adjustment)


Water for injections

Elderly
No dose adjustment is necessary.

Pediatric
Safety and efficacy have not been established.

Renal Impairment
No dose adjustment in mild to moderate renal impairment.
There are limited data in severe renal impairment.

Hepatic Impairment
No dose adjustment in mild hepatic impairment.
Caution in moderate hepatic impairment: bilirubin > 1,5-3 upper limit of normal (ULN).
Limited data available in patients with severe hepatic impairment: bilirubin > 3 ULN.

Immunisations
Live vaccines should not be applied while taking the treatment or for at least 6 months
afterwards. Other vaccines can be administered, though may not give as much protection as
usual. In any case, it is safe to be in contact with other people who have had live vaccines as
injections. There can be problems with oral vaccines. Any contacts with someone who has
had oral polio, cholera or typhoid vaccination recently, should be avoided.

Pregnancy
Unknown risk for the fetal development. Recommended effective contraception while on
the treatment and at least for 5 months following the last dose.

Breast-Feeding
Unknown if nivolumab is excreted in maternal milk, but due to the potential adverse
effects in the baby, it is advisable to stop nursing while on the treatment.

Warnings [5-7]

Immune-mediated adverse reactions


Hepatitis
Monitor liver function.
Stop the treatment if moderate.
Permanently discontinue if severe or life-threatening.
Nephritis and renal dysfunction
Monitor renal function.
Stop the treatment if moderate.
Permanently discontinue if severe or life-threatening.
Nivolumab. Opdivo® 277

Pneumonitis
Stop the treatment if moderate.
Permanently discontinue if severe or life-threatening.
Colitis
Stop the treatment if moderate.
Permanently discontinue if severe or life-threatening.
Hypothyroidism and hyperthyroidism
Monitor thyroid function.
Initiate thyroid hormone replacement as needed.

TOXICITY [6, 7]
Organic system disorders Very Common Common ≥ 1/1000 to < Uncommon
≥ 1/10 1/10 ≥ 1/1,000 to <1/1000
Infections and Upper respiratory
Infestations disorders infections
Immunological disorders Infusion related reaction Anaphylactic reaction
Endocrine disorders Hypothyroidism, Adrenal insufficiency,
hyperthyroidism, hypopituitarism,
hyperglycemia hypophysitis, thyroiditis,
diabetes mellitus, diabetic
cetoacidosis
Nervous system Peripheral neuropathy, Guillain-Barre syndrome,
disorders headache, dizziness myastenia, autoimmune
neuropathy (facial nerves
paralysis)
Blood and lymphatic Hyponatremia
system disorders
Eye disorders Uveitis
Renal and urinary disorders Renal insufficiency,
tubulointerstitial nephritis
Respiratory, thoracic Pneumonitis, dyspnea,
and mediastinal cough
disorders
Gastrointestinal Diarrhoea, nauseas Colitis, stomatitis, Pancreatitis
disorders abdominal pain,
constipation, vomiting
Skin and Itchiness, cutaneous Vitiligo, skin dryness, Multiforme erythema,
subcutaneous tissue eruption erythema, alopecia psoriasis, rosacea
disorders
Cardiovascular disorders Arrhythmia including
ventricular, hypertension
Investigations AST elevation, ALT Lipase elevation, amylase
elevation, bilirubin elevation, neutropenia
elevation, alkaline
phosphatase elevation,
creatinine elevation,
lymphopenia,
thrombocytopenia,
anaemia
Musculoskeletal and Musculoskeletal pain,
connective tissue arthralgia
disorders
General disorders and Fatigue Anorexia, pirexia, oedema
administration site conditions
278 E. Una Cidon

DOSE MODIFICATIONS [6-7]


It is not recommended a reduction in the dose. It may be necessary a delay or an
interruption in the treatment.

Toxicity Grade Dose modification


Colitis or Grade 2 or 3 Stop treatment until symptoms resolve and steroids
nephritis treatment is finished
Grade 4 Permanent discontinuation
Hepatitis Grade 2 Stop treatment until symptoms resolve and steroids
treatment is finished
Grade 3 or 4 Permanent discontinuation
Pneumonitis Grade 2 Stop treatment until symptoms resolve and steroids
treatment is finished
Grade 3 or 4 Permanent discontinuation
Cutaneous Grade3 Stop treatment until symptoms resolve and steroids
eruption treatment is finished
Grade 4 Permanent discontinuation
Endocrinopathy Stop treatment until symptoms resolve and steroids
treatment is finished.
Nivolumab should continue with hormonal replacement
until symptoms have gone

INTERACTIONS [6-7]
Nivolumab is a monoclonal antibody and thus, it is not metabolized by cytochrome p450.
Avoid use of systemic steroids and other immunosuppressive agents before starting
nivolumab, though they can be used while on treatment to treat adverse reactions as they do
not seem to interfere with the response to nivolumab.

CONCLUSION
Nivolumab is a human monoclonal antibody that blocks the interaction between PD-1
and its ligands, PD-L1 and PD-L2. The drug is administered intravenously (iv). In phase I/II
studies it has shown promising activity and safety and ongoing phase III trials are comparing
nivolumab with other standard of care therapies (chemotherapy, ipilimumab) for melanoma.
The efficacy may be even higher when used in combination with ipilimumab (although the
toxicity will increase) [1].
Among patients with advanced, previously treated squamous-cell non-small cell lung
carcinoma (NSCLC), overall survival, response rate, and progression-free survival were
significantly better with nivolumab than with docetaxel, regardless of PD-L1 expression
level. Among patients with advanced nonsquamous NSCLC that had progressed during or
after platinum-based chemotherapy, overall survival was longer with nivolumab than with
docetaxel [1-3].
Nivolumab. Opdivo® 279

In contrast to typical short-lived responses with cancer therapy in metastatic solid


tumours, many responses induced by nivolumab appear durable [1-4].
In patients with previously treated advanced renal-cell carcinoma, overall survival was
longer and fewer grade 3 or 4 adverse events occurred with nivolumab than with everolimus
[4].
Overall, the toxicity profile with this drug is manageable. Ongoing trials are investigating
its potential role alone or in combination with other therapies in multiple cancer settings
[1-4].

REFERENCES
[1] Douglas B. Johnson, Chengwei Peng, and Jeffrey A. Sosman. Nivolumab in melanoma:
latest evidence and clinical potential. Ther Adv Med Oncol. 2015 Mar; 7(2): 97–106.
[2] Brahmer J, Reckamp K, Baas P, Crinò L, Wilfried E.E, Eberhardt E, Poddubskaya E,
Antonia S, Pluzanski A, Vokes E, Holgado E, Waterhouse D, Ready N, Gainor J,
Frontera O, Havel L, Steins M, Garassino M, Aerts J, Domine M, Paz-Ares L, Reck M,
Baudelet C, Harbison C, Lestini B, Spigel D. Nivolumab versus Docetaxel in Advanced
Squamous-Cell Non–Small-Cell Lung Cancer. N Engl J Med 2015; 373:123-135.
[3] Borghaei H, Paz-Ares L, Horn L, Spigel D, Steins M, Ready N, Chow L, Vokes E, Felip
E, Holgado E, Barlesi F, Kohlhäufl M, Arrieta O, Burgio M, Fayette J, Lena H,
Poddubskaya E, Gerber D, Gettinger S, Rudin CM, Rizvi N, Crinò L, Blumenschein G,
Antonia S, Dorange C, Harbison C, Finckenstein F, Brahmer J. Nivolumab versus
Docetaxel in Advanced Non-squamous Non–Small-Cell Lung Cancer. N Engl J Med
2015; 373:1627-1639.
[4] Motzer R, Escudier B, McDermott D, George S, Hammers H, Srinivas S, Tykodi S,
Sosman J, Procopio G, Plimack E, Castellano D, Choueiri T, Gurney H, Donskov F,
Bono P, Wagstaff J, Gauler T, Ueda T, Tomita Y, Schutz F, Kollmannsberger C, Larkin
J, Ravaud A, Simon J, Xu L, Waxman I, Sharma P. Nivolumab versus Everolimus in
Advanced Renal-Cell Carcinoma. N Engl J Med 2015; 373:1803-1813.
[5] Nivolumab-Medscape Reference; http://reference.medscape.com/drug/opdivo-
nivolumab-999989.
[6] Opdivo (nivolumab) injection Label - Food and Drug Administration;
http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/125554lbl.pdf
[7] Nivolumab BMS, INN-nivolumab - Europa; http://ec.europa.eu/health/documents
/community-register/2015/20150720132394/anx_132394 _es.pdf.
In: The Easy Book of Cancer Pharmacology ISBN: 978-1-63485-038-4
Editor: Esther Una Cidon © 2016 Nova Science Publishers, Inc.

Chapter 32

OXALIPLATIN. 1-OHP, L-OHP, OXALATOPLATIN,


OXALIPLATINUM, ELOXATIN®

M. Luque Cabal1, and P. Garcia Teijido2


1
Medical Oncology Department, University Hospital of Asturias, Oviedo, Spain
2
Medical Oncology Department, ―San Ag ustin‖ Hospital, Aviles, Spain

ABSTRACT
Oxaliplatin is a platinum complex that is used in conjunction with different
chemotherapies for the treatment of various cancers, mainly colorectal adenocarcinoma,
but also pancreatic, esophagogastric and ovarian tumours. Its chemical structure confers
it different pharmacokinetic properties and clinical utility. Thus, it is active in colon
cancer, a tumor in which neither cisplatin nor carboplatin are useful, and in cisplatin-
resistant models in vitro. Its main mechanism of action is similar to other platinum
derivatives. Real or potential synergism has been observed when oxaliplatin is combined
with other cytotoxic agents or molecularly targeted agents. The toxicity profile for
oxaliplatin includes nausea, vomiting, hematologic effects, diarrhea and peripheral
sensory neuropathy, which is dose limiting.

Keywords: oxaliplatin, colon cancer, eloxatin

INTRODUCTION
Oxaliplatin is part of the ‗DACH‘ family of platinum analogs. This group of platinum
compounds was first synthesized in 1972 by substituting the amine radicals of cisplatin with a
dyaminociclohexane (DACH) radical. The prototypes of this group showed promising anti-
tumor activity but low solubility in water, limiting their potential use in the clinic.
Modifications to improve water solubility were made and oxaliplatin was first synthesized in
the late 1970s [1].


Maria Luque Cabal, e-mail: malucabal@yahoo.es.
282 M. Luque Cabal and P. Garcia Teijido

The chemical structure of oxaliplatin or oxalate (transl-1,2 diaminocyclohexane)


platinum, differs from cisplatin in that the amine groups of cisplatin are replaced by the
DACH carrier ligand and the presence of an oxalate ―l eaving group.‖ This structure
determines different properties: unlike cisplatin, oxaliplatin in plasma rapidly undergoes non-
enzymatic transformation into reactive compounds because of displacement of the oxalate
group; it is active in colon cancer and it is non-cross-resistant with some platinum-resistant
experimental tumor systems.

CLINICAL PHARMACOLOGY
Drug Classification

Platinum analog.

Mechanism of Action [2]

1. DNA lesions: Oxaliplatin exerts its cytotoxic effect mostly through DNA damage,
like other platinum-based compounds. Intra-strand crosslinks seem to be the
predominant mechanism of action in the induction of DNA lesions, with binding of
two Gs, or less frequently, a G–A base pair, whereas inter-strand crosslinks
contribute less unlike cisplatin. Lethal DNA biadducts inhibit both DNA replication
and transcription, causing apoptosis after cell cycle arrest unless nucleotide excision
repair has occurred. The conformation of oxaliplatin adducts, as compared with those
of cisplatin or carboplatin adducts, makes binding with the mismatch repair (MMR)
protein complex more difficult, presumably resulting in greater irreversibility of the
lesions. In addition, the bulky DACH compound is postulated to more effectively
prevent DNA synthesis than does the cis-diamine carrier ligand of cisplatin.
2. Arrest of DNA synthesis by a direct inhibitory effect of oxaliplatin on thymidylate
synthase.
3. Inhibition of transcription by three main mechanisms:
 Some transcription factors may have chemical affinity form platinum, so they
bind to DNA adducts and therefore binding to their promoter site is prevented.
 Inhibition of RNA polymerases
 The nucleosomal DNA adducts have the potential to block access by the RNA
polymerase to the DNA template
4. Immunologic mechanisms: In vitro, oxaliplatin can cause the immunogenic death of
colon cancer cells. After exposure to oxaliplatin, colon cancer cells emit several
immunogenic signals on their surface before undergoing apoptosis. These signals
trigger the production of interferon γ by T cells and also interact with the toll-like
receptor 4 of dendritic cells, the whole process resulting in a sort of tumor vaccine.
Oxaliplatin. 1-OHP, L-OHP, Oxalatoplatin, Oxaliplatinum, Eloxatin® 283

Pharmacokinetics [3]

Absorption Not applicable as intravenous (iv) administration


Distribution 15% of the administered platinum is present in the systemic circulation.
85% is rapidly distributed into tissues or eliminated in the urine.
Plasma protein binding: 70-95%
It also accumulates in erythrocytes (which act as a drug reservoir).
It does not cross blood-brain barrier.
Metabolism Rapid and extensive non-enzymatic biotransformation to reactive platinum complexes.
No evidence of cytochrome P450 mediated metabolism in vitro.
Several platinum containing-derivatives have been identified in plasma ultrafiltrate,
some cytotoxic (monochloro DACH platinum, dichloro DACH platinum, that causes
neurotoxicity, and monoaquo and diaquo DACH platinum) and others non-cytotoxic
conjugated species.
Excretion Main route: renal excretion.
At five days after a single 2-hour infusion, urinary elimination accounted for about 54%
of the platinum eliminated, with fecal excretion accounting for only about 2%.
Platinum was cleared from plasma at a rate (10-17 L/h) that was similar to or exceeded
the average human glomerular filtration rate (GFR; 7.5 L/h).
No significant effect of gender on the clearance of ultrafilterable platinum. The renal
clearance of ultrafilterable platinum is significantly correlated with GFR.

Mechanism of Resistance [2]

Many mechanisms of resistance have been described or hypothesized because of


similarity between oxaliplatin and cisplatin. The intracellular fate of the drug can be affected
by decreased uptake (resulting in lower intracellular concentration) or inactivation by
structural or spatial changes (conjugation with glutathione or sequestration with
metallothionein). However, the most important mechanisms seem to be related to DNA
repair: MMR, or nucleotide excision repair (NER). Cells that overexpress ERCC1, an
excision repair enzyme, are resistant to oxaliplatin.
Pre-clinical data suggests that there is cross-resistance between cisplatin and oxaliplatin
in low-level resistance models. However, in models with high level resistance (>10-fold)
there is less cross-resistance between both platins. Therefore, oxaliplatin was thought to be
active in cisplatin- resistant cancer. Anyway, in clinical trials, oxaliplatin activity was clearly
higher in platinum-sensitive cancers than in those platinum-refractory. This suggests that
there may be, at least, partial cross-resistance between both agents in the clinic [4].

Indications

1. Adjuvant treatment of stage III colorectal cancer in patients who have undergone
complete resection of the primary tumor [3].
2. Treatment of advanced colorectal cancer.
3. Other uses:
 As part of the FOLFIRINOX regimen for treatment of advanced pancreatic
cancer [5].
284 M. Luque Cabal and P. Garcia Teijido

 In combination with epirubicin plus either fluorouracil or capecitabine for


advanced esophagogastric cancer [6].
4. In combination with other drugs for ovarian cancer previously treated with cisplatin
or carboplatin [7-10].

Dosages

 In Combination with 5-Fluorouracil and Leucovorin: 85 mg/m2 IV infusion over 2


hours every 2 weeks
 In combination with capecitabine: 130 mg/m2 IV infusion over 2-6 hours every 3
weeks.

Methods of Preparation/Administration [3]

Do not freeze and protect from light the concentrated solution.


A final dilution must never be performed with a sodium chloride solution or other
chloride-containing solutions. The solution must be further diluted in an infusion solution of
250-500 mL of 5% Dextrose Injection. It is incompatible in solution with alkaline
medications or media (such as basic solutions of 5-fluorouracil) and must not be mixed with
these or administered simultaneously through the same infusion line.
Needles or iv administration sets containing aluminum parts that may come in contact
with oxaliplatin should not be used for the preparation or mixing of the drug [3].

 Oxaliplatin should always be administered before 5-fluorouracil.

Prolongation of infusion time for oxaliplatin from 2 hours to 6 hours may mitigate acute
pharyngolaryngeal dysesthesia.
In case of extravasation, immediately interrupt the administration (See warnings section).

Special Information and Cautions

Contraindications
 Hypersensitivity to the active drug or to its excipients.
 Peripheral sensitive neuropathy with functional impairment before initiating the
treatment.
 Severe renal impairment (creatinine clearance <30 mls/min).

Elderly
It has not been observed any significant effect of age on the clearance of ultrafilterable
platinum though elderly patients have a higher incidence of GI toxicity, myelosuppression,
syncope and fatigue.
No starting dose adjustments are needed but caution should be exercised.
Oxaliplatin. 1-OHP, L-OHP, Oxalatoplatin, Oxaliplatinum, Eloxatin® 285

Pediatric
The effectiveness of oxaliplatin in children has not been established.

Renal Impairment
Clearance of ultrafilterable platinum is decreased in patients with mild, moderate, and
severe renal impairment. Caution should be applied when using this agent in patients with
renal impairment.
The starting oxaliplatin dose does not need to be reduced in patients with mild (creatinine
clearance = 50-80 mL/min) or moderate (creatinine clearance = 30-49 mL/min) renal
impairment. However, it is not recommended in patients with severe renal impairment
(creatinine clearance <30 mL/min) [3].

Hepatic Impairment
No adjustment required for mild to moderate liver impairment; no information found
regarding severe hepatic insufficiency.

Immunizations
Live vaccines should not be applied while taking the treatment or for at least 6 months
afterwards. Other vaccines can be administered, though may not give as much protection as
usual.
In any case, it is safe to be in contact with other people who have had live vaccines as
injections. There can be problems with oral vaccines. Any contacts with someone who has
had oral polio, cholera or typhoid vaccination recently, should be avoided.

Warnings

Pulmonary Toxicity
Until interstitial lung disease or pulmonary fibrosis are ruled out, oxaliplatin needs to be
discontinued.

Allergic Reactions
Monitor for development of rash, urticaria, erythema, pruritis, bronchospasm and
hypotension.

Neuropathy
Dose needs to be reduced or oxaliplatin stopped.

Hepatotoxicity
Liver tests should be monitored.

Pregnancy
Fetal harm can occur. Effective anticonceptive methods should be used.
286 M. Luque Cabal and P. Garcia Teijido

Extravasation [11, 12]


Oxaliplatin may be included as an irritant or as a vesicant. Guidelines recommend the
following steps at the first sign of infiltration or extravasation:

 Stop administration immediately, disconnect the iv tubing from the device, attempt
aspiration of the residual drug from the iv device.
 Although optimal management remains uncertain, it should include:
 Warm compresses (cold may aggravate neuropathy)
 Sodium thiosulfate 0.16 Molar (mole/liter) injected subcutaneously into the
extravasation site has been reported as effective in case reports of oxaliplatin
extravasation. This is prepared by mixing 4 mL sodium thiosulfate 10% solution
with 6 mL sterile water for injection. The solution (5 mL) is injected
subcutaneously into the extravasation site. Its use is not confirmed by clinical
trials.
 Oral dexamethasone for 10-14 days after oxaliplatin extravasation may reduce
inflammation.

Toxicities [2, 3, 13]

System organ Very common Common Uncommon Rare (≥1/10,000


class (≥1/10) (≥1/100 to <1/10) (≥1/1000 to <1/100) and <1/1000)
Skin disorders Hand-foot
syndrome, rash, nails
disorders
Infections and Infections Sepsis, febrile
infestation neutropenia
disorders
Nervous system Peripheral sensory Dizziness, motor Guillain-Barre
disorders neuropathy neuritis, syndrome,
exacerbated by meningismus, visual Reversible
exposure to cold, disorders Posterior
pharyngolaryngeal Leukoencephalo-
dysesthesia, headache pathy Syndrome
(RPLS)
Psychiatric Depression,
disorders insomnia
Vascular Hypertension,
disorders venous thrombo-
embolism
Gastrointestinal Diarrhea, constipation, Dyspepsia, GI obstruction, Pancreatitis
disorders stomatitis, dysgeusia, esophageal reflux gastro-intestinal
nausea, vomiting hemorrhage
Hepatobiliary Elevation in liver Hepatic veno-
disorders function tests occlusive disease
Respiratory, Cough, dyspnea Pneumonitis Pulmonary fibrosis
thoracic and
mediastinal
disorders
Oxaliplatin. 1-OHP, L-OHP, Oxalatoplatin, Oxaliplatinum, Eloxatin® 287

System organ Very common Common Uncommon Rare (≥1/10,000


class (≥1/10) (≥1/100 to <1/10) (≥1/1000 to <1/100) and <1/1000)
Renal and Urinary symptoms Nephrotoxicity Hemolytic uremic
urinary disorders syndrome/
microangiopathic
General Injection site reaction, Rhinitis, dehydration
disorders and anorexia, fatigue
administration
site conditions
Investigations Hypernatremia,
hypokalemia
Blood disorders Anemia, INR/prothrombin Idiopathic
thrombocytopenia, time increased thrombocytopenic
leucopenia, purpura, hemolysis
neutropenia, (immune hemolytic
lymphopenia anemia)
Musculoskeletal Back pain Rhabdomyolysis
disorders
Hearing and eye Conjunctivitis Watery eyes Hearing impaired,
disorders transient vision loss
Immunological Allergies,
disorders hypersensitivity
reactions

Note

Patients should be informed about the persistence of peripheral sensitive neuropathy after
finishing the treatment. Moderate paresthesias may interfere with functional activities and last
for three years.

Dose Modifications [3, 4]

Toxicity Dose adjustment


Persistent Sensory neuropathy
Grade 2 Adjuvant treatment: dose reduction to 75
mg/m2 every 2 weeks
Grade 2 Advanced disease: dose reduction to 65 mg/m2
every 2 weeks
Grade 3 Discontinue
Grade 3-4 gastrointestinal toxicity or grade 4 Dose reduction to 65 mg/m2 every 2 weeks
neutropenia and 5-fluorouracil dose reduction by 20%
Sepsis/septic shock/RPLS/Hemolytic uremic syndrome Discontinue
or any signs of microangiopathic hemolytic anemia
Other ≥ grade 3 toxicity Consider dose reduction/discontinue treatment
288 M. Luque Cabal and P. Garcia Teijido

Interactions [3]

No specific cytochrome P-450-based drug interaction studies have been conducted.


Increases of 5-fluorouracil plasma concentrations by approximately 20% have been
observed with doses of 130 mg/m2 every 3 weeks.
Because platinum-containing species are eliminated primarily through the kidney,
clearance of these products may be decreased by co-administration of potentially nephrotoxic
compounds.

CONCLUSION
Oxaliplatin is the only platinum analog with antitumor activity in colon carcinoma, which
is its main indication, although it has efficacy in other tumors. Among its toxicities,
peripheral sensory neuropathy is often dose-limiting although it is usually reversible.

REFERENCES
[1] Rixe O, Ortuzar W, Alvarez M, Parker R, Reed E, Paull K et al. Oxaliplatin, tetraplatin,
cisplatin, and carboplatin: spectrum of activity in drug-resistant cell lines and in the cell
lines of the National Cancer Institute‘s Anticancer Drug Screen panel. Biochem
Pharmacol 1996;52:1855-65.
[2] Alcindor T, Beauger N. Oxaliplatin: a review in the era of molecularly targeted therapy.
Current Oncology 2011;18:18-25.
[3] ELOXATIN® (oxaliplatin) injection for intravenous use Prescribing Information. http://
products.sanofi.us/eloxatin/eloxatin.html [30/05/2015 16:43:07].
[4] Stordal B, Pavlakis N, Davey R. Oxaliplatin for the treatment of cisplatin-resistant
cancer: A systematic review. Cancer Treatment Reviews 2007; 33: 347-357.
[5] Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y et al.
FOLFIRINOX versus Gemcitabine for Metastatic Pancreatic Cancer. N Engl J Med
2011; 364:1817-1825.
[6] Cunningham D, Starling N, Rao S, Iveson T, Nicolson M, Coxon F, Middleton G,
Daniel F, Oates J, Norman AR; Upper Gastrointestinal Clinical Studies Group of the
National Cancer Research Institute of the United Kingdom. Capecitabine and
oxaliplatin for advanced esophagogastric cancer. N Engl J Med. 2008;358(1):36-46.
[7] Taylor SE, Beck TL, Krivak TC, Zorn KK, Kelley JL, Edwards RP. Oxaliplatin salvage
for recurrent ovarian cancer: a single institution‘s experience in patient populations with
platinum resistant disease or a history of platinum hypersensitivity. Gynecol Oncol.
2014 Jul;134(1):68-72.
[8] Stein SM, Tiersten A, Hochster HS, Blank SV, Pothuri B, Curtin J, Shapira I, Levinson
B, Ivy P, Joseph B, Guddati AK, Muggia F. A phase 2 study of oxaliplatin combined
with continuous infusion topotecan for patients with previously treated ovarian cancer.
Int J Gynecol Cancer. 2013 Nov;23(9):1577-82.
Oxaliplatin. 1-OHP, L-OHP, Oxalatoplatin, Oxaliplatinum, Eloxatin® 289

[9] Vici P, Sergi D, Pizzuti L, Mariani L, Arena MG, Barba M, Maugeri-Saccà M,


Vincenzoni C, Vizza E, Corrado G, Paoletti G, Tomao F, Tomao S, Giannarelli D, Di
Lauro L. Gemcitabine-oxaliplatin (GEMOX) as salvage treatment in pretreated
epithelial ovarian cancer patients. J Exp Clin Cancer Res. 2013 Aug. 8;32(1):49.
[10] Lee HJ, Kim HS, Park NH, Chung HH, Kim JW, Song YS. Feasibility of Oxaliplatin,
Leucovorin, and 5-Fluorouracil (FOLFOX-4) Chemotherapy in Heavily Pretreated
Patients with Recurrent Epithelial Ovarian Cancer. Cancer Res Treat. 2013 Mar;45(1):
40-7.
[11] Doellman D, Hadaway L, Bowe-Geddes LA et al. Infiltration and extravasation: Update
on prevention and management. J Infus Nurs. 2009;32:203-211.
[12] sanofi-aventis. Eloxatin prescribing information, 2009. Available at http://products.
sanofi-aventis.us/eloxatin/eloxatin.pdf Accessed February 18, 2010.
[13] Cancer Care Ontario-Oxaliplatin. April 2015. https://cancercare.on.ca/CCO_Drug
Formulary/pages/DfPdfContent.aspx?cat=DM&name=oxaliplatin.
In: The Easy Book of Cancer Pharmacology ISBN: 978-1-63485-038-4
Editor: Esther Una Cidon © 2016 Nova Science Publishers, Inc.

Chapter 33

PACLITAXEL: TAXOL

E. Una Cidon1, and A. Ballesteros2


1
Medical Oncology Department, Royal Bournemouth Hospital NHS Foundation Trust,
Bournemouth, UK
2
Oncology Pharmacy, Poole Hospital NHS Foundation Trust, Poole, UK

ABSTRACT
Paclitaxel is a member of the taxanes family which has demonstrated encouraging
activity in human malignancies. This drug has got a unique mechanism of action which
eventually induces mitotic arrest by blocking cells in the G2/M phase of the cell cycle. It
enhances the polymerization of tubulin to stable microtubules and also interacts directly
with microtubules, stabilizing them against depolymerization. It is approved by the Food
and Drug Administration (FDA) to treat ovarian, non-small cell lung cancer (NSCLC),
breast and Kaposi‘s sarcoma but it is used off-label to treat gastroesophageal,
endometrial, cervical, prostate and head and neck tumours

Keywords: paclitaxel, taxanes, microtubules

INTRODUCTION
Paclitaxel is better known as Taxol and it is the first member of the taxanes family to be
used in the treatment of cancer. This agent exerts its cytotoxic effect by arresting mitosis
through microtubule stabilization, resulting in cellular apoptosis. Paclitaxel is widely used in
the treatment of many types of cancer such as ovarian, breast and NSCLC. However,
significant toxicities, such as myelosuppression and peripheral neuropathy, may limit the
effectiveness of this treatment


E. Una Cidon, aunacid@hotmail.com; Esther.unacidon@rbch.nhs.uk.
292 E. Una Cidon and A. Ballesteros

CLINICAL PHARMACOLOGY
Drug Classification

Antineoplastic agent, antimicrotubule.

Mechanism of Action

Paclitaxel is a novel antimicrotubule agent that promotes the assembly of microtubules


from tubulin dimers and stabilizes microtubules by preventing depolymerization. This
stability results in the inhibition of the normal reorganization of the microtubules that is
essential for mitotic cellular functions. In addition, the cytoskeleton is reorganized in the
presence of paclitaxel and stable bundles of microtubules are formed in cells growing in
tissue culture. Paclitaxel blocks cells in the G2/M phase of the cell cycle leading to apoptosis
[3]

Pharmacokinetics [4]

Absorption Not applicable


Distribution Protein bound: 89-98%
Volume of distribution: 227-688 L/m²
Metabolism Liver metabolism by CYP2C8, CYP3A4
Major metabolite is 6-alpha-hydroxypaclitaxel
Excretion Half-life is 27hr terminal
Faeces (20%)
Urine (4%)

Indications [4]

Ovarian Cancer
First line in combination with cisplatin for advanced ovarian carcinoma.
Second line after failure of first line with platin derivatives.

Breast Cancer
Node positive as adjuvant chemotherapy after anthracyclines and cyclophosphamide.
Locally advanced or metastatic disease after failure of initial chemotherapy. It could be
combined with trastuzumab for patients with overexpression of Her-2. It could be used as
monotherapy for patients not candidates to standard therapy with anthracyclines.

NSCLC
In combination with cisplatin for patients not candidates for curative surgery or
radiotherapy.
Paclitaxel: Taxol 293

AIDS-Related Kaposi’s Sarcoma (2nd Line Therapy)


After a failure of the first line with liposomal anthracycline.

Off-Label Indications
Head/neck cancer, small-cell lung cancer, upper GI adenocarcinoma, hormone-refractory
prostate cancer, Non-Hodgking Lymphoma, urothelium transitional cell carcinoma, stage IIB-
IV melanoma.

Dosages [4, 5]

Ovarian Cancer
Previously untreated: 175 mg/m² IV over 3 hours q3Weeks (followed by cisplatin)
Previously treated: 135 mg/m² IV q3Weeks (follow with cisplatin)

Breast Cancer
175 mg/m² IV over 3 hours q3 Weeks

AIDS-Related Kaposi’s Sarcoma (2nd Line Therapy)


135 mg/m² IV over 3 hours q3 Weeks
100 mg/m² IV over 3 hours q2 Weeks

Methods of Preparation/Administration [4, 5]

Prior to infusion, paclitaxel must be diluted using an aseptic technique with a solution of
0.9% sodium chloride, or 5% glucose or a mixture of 5% glucose and 0.9% saline or Ringer's
solution infusion of 5% glucose to a final concentration of 0.3 to 1.2 mg/ml.
Paclitaxel should be administered through an inline filter with a microporous
membrane ≤0.22 micron as soon as the solution is prepared. To reduce the risk of
precipitation, paclitaxel should be administered as soon as possible after dilution, and
excessive agitation, vibration or shaking should be avoided.
The infusion equipment should be washed thoroughly before use. During perfusion the
aspect of the solution should be examined regularly and, if precipitation, the infusion should
be stopped. To minimize patient exposure to di-(2-ethylhexyl) phthalate (DEHP) which may
be leached from polyvinyl chloride (PVC) bags, paclitaxel should be kept in containers
without PVC.
Prior to the administration of Paclitaxel, all patients should receive premedication with
corticosteroids, antihistamines and H2 antagonists.
294 E. Una Cidon and A. Ballesteros

Special Information and Cautions [4, 5]

Contraindications

 Hypersensitivity to the drug or the excipients listed below especially the ricinoleate
macrogolglycerol.

Excipients
Ricinoleate Macrogolglycerol
Ethanol 96%
Anhydrous citric acid (E330) for pH adjustment

 Pregnancy and breast-feeding.


 Baseline neutrophils <1500 cells/m³
 AIDS-related Kaposi's sarcoma with baseline neutrophils <1000 cells/m³

Elderly [6]
Pharmacokinetic in elderly does not appear to differ from younger.

Pediatric
Safety and efficacy not definitively established.

Renal
No dose adjustment is necessary.

Hepatic
Severe hepatic insufficiency should not be treated with paclitaxel. Available data are not
sufficient to advice a dose modification in moderate or mild hepatic impairment.

Immunisations
Live vaccines should not be applied while taking the treatment or for at least 6 months
afterwards. Other vaccines can be administered, though may not give as much protection as
usual.
In any case, it is safe to be in contact with other people who have had live vaccines as
injections. There can be problems with oral vaccines. Any contacts with someone who has
had oral polio, cholera or typhoid vaccination recently, should be avoided.

Pregnancy
Paclitaxel has been shown to be clastogenic, teratogenic and fetotoxic and should not be
used in pregnancy. Men should be advised not to father a child while receiving treatment.

Breast-Feeding
It is not known if paclitaxel is excreted in human milk; however, it is recommended that
nursing should be discontinued during therapy.
Paclitaxel: Taxol 295

Warnings [4]

Hypersensitivity
Pretreat all patients with corticosteroids, diphenhydramine, and H2 antagonists.
Do not re-challenge patients who experience severe hypersensitivity reactions to the drug.
Fatal anaphylaxis and severe hypersensitivity reactions characterized (dyspnea and
hypotension requiring treatment, angioedema and generalized urticarial) have been seen in
patients despite premedication.

Neutrophils
Monitor blood counts to look for neutropenia, which may result in infection.

Toxicities [4]
Organic disorders Very common Common Uncommon Rare Very rare
(≥1/10) (>1/100 to (≥1/1000 to (≥1/10,000 to
<1/10) <1/100) <1/1000)
Infections and UTI, upper Septic shock Pneumonia,
infestations respiratory peritonitis, sepsis
infection
Blood and Myelosuppression, Febrile Myelodysplastic
lymphatic disorders neutropenia, neutropenia syndrome, acute
anaemia, myeloid leukemia.
thrombocytopenia,
leucopenia,
bleeding
Immunological Hypersensitivity Hypersensitivity Anaphylactic Anaphylactic shock
disorders (usually mild) severe with reactions
hypotension,
respiratory
distress, back
pain, limbs pain,
hypertension,
tachycardia, chest
pain …
Nutritional and Anorexia
metabolic disorders
Nervous system Neurotoxicity Motor neuropathy Confusion,
disorders (peripheral autonomous
neuropathy) neuropathy (ileo
paralyticus,
ortostatic
hypotension),
epileptic episodes,
encephalopathy,
dizziness,
headaches, ataxia.
Ocular disorders Visual disturbances
or optic nerve
disturbances
(scotomas)
Ear disorders Ototoxicity, tinnitus,
vertigo
Vascular disorders Hypotension Hypertension, Shock
thrombosis,
thrombophlebitis
296 E. Una Cidon and A. Ballesteros

(Continued)

Organic disorders Very common Common Uncommon Rare Very rare


(≥1/10) (>1/100 to (≥1/1000 to (≥1/10,000 to
<1/10) <1/100) <1/1000)
Respiratory and Dyspnea, pleural Cough
thoracic disorders effusion, interstitial
pneumonia, lung
fibrosis, pulmonary
embolism,
respiratory
insufficiency
Gastrointestinal Nausea, vomiting, Intestinal Pseudomembranose
disorders diarrhoea, obstruction, colitis, esophagitis,
mucositis perforation, constipation,
ischaemic colitis, ascites, neutropenic
pancreatitis colitis, mesenteric
thrombosis
Hepatobiliary Liver necrosis,
disorders hepatic
encephalopathy
Skin and hair alopecia Mild nail Itchiness, rash, Stevens-Johnsons‘s
disorders alterations erythema syndrome,
epidermic
necrolysis, urticary,
onycholysis,
Musculoskeletal Arthralgia,
disorders myalgia
General disorders Injection site Fatigue, pyrexia,
erythema dehydration, edema,
(localised general malaise
edema,
erythema,
induration
…)
Investigations Elevation Elevation of Elevation of
AST, alkaline bilirubin creatinine
phosphatase

Dose Modifications [4, 5]

Hepatic Impairment
Transaminases Dosage
AST/ALT < 10 x ULN 175 mg/m² over 3 hr
Bilirubin < 1.25 x ULN
AST/ALT < 10 x ULN 135 mg/m² over 3 hr
Bilirubin 1.26-2 x ULN
AST/ALT < 10 x ULN 90 mg/m² over 3 hr
Bilirubin 2.01-5 x ULN
AST/ALT ≥ 10 x ULN or Do not administer
Bilirubin > 5 x ULN

Neutropenia
Patients who experiences severe neutropenia (<500 cells/mm³ for a week or longer), or
severe peripheral neuropathy during therapy should have the dose reduced by 20% for
subsequent courses of therapy.
Paclitaxel: Taxol 297

Interactions [4]

Ketoconazole is a known potent inhibitor of CYP3A4 but it does not inhibit the
elimination of paclitaxel in patients; so both drugs may be administered together without dose
adjustment.
Caution should be taken into account when administering together with CYP3A4
inhibitors such as erythromycin, fluoxetine, gemfibrozil or CYP3A4 inducers such as
rifampicin, carbamazepine, phenytoin, phenobarbital, efavirenz, nevirapine and with CYP2C8
or CYP3A4.
Several studies suggest that paclitaxel clearance is significantly lower with nelfinavir and
ritonavir, but not with indinavir. The available information on interactions with other protease
inhibitors is insufficient.

CONCLUSION
Paclitaxel is a member of the taxanes family which has demonstrated encouraging
activity in several human malignancies. It will eventually induce mitotic arrest by blocking
cells in the G2/M phase of the cell cycle. Paclitaxel will enhance the polymerization of
tubulin to stable microtubules and also interacts directly with microtubules, stabilizing them
against depolymerization. Paclitaxel is better known as Taxol and it is the first member of the
taxanes family to be used in the treatment of cancer. However, significant toxicities, such as
myelosuppression and peripheral neuropathy, may limit the effectiveness of this
treatment

REFERENCES
[1] Beth A. Weaver. How Taxol/paclitaxel kills cancer cells. Mol Biol Cell. 2014;
25(18):2677-2681.
[2] Marupudi N. I., Han J. E., Li K. W., Renard V. M., Tyler B. M., Brem H. Paclitaxel: a
review of adverse toxicities and novel delivery strategies. Expert Opin Drug Saf. 2007;
6(5):609-621.
[3] Horwitz S. B. Taxol (paclitaxel): mechanisms of action. Ann Oncol. 1994; 5 Suppl
6:S3-6.
[4] Paclitaxel ficha tecnica. http://www.aemps.gob.es/cima/pdfs/es/ft/67854/FT_67854.
pdf. Spanish.
[5] Paclitaxel dosage guide with precautions. http://www.drugs.com/dosage/paclitaxel.
html.
[6] Panos F., Jeffrey G., Supko R. M., Boral A., Carey R., Grossbard M., Shapiro G.,
Ostler P., Lucca J., Bruce E., Skarin A., Lynch A. A Phase II Study of Weekly
Paclitaxel in Elderly Patients with Advanced Non-Small Cell Lung Cancer. Clinical
Cancer Research. 2001; 2(7):3942-3949.
In: The Easy Book of Cancer Pharmacology ISBN: 978-1-63485-038-4
Editor: Esther Una Cidon © 2016 Nova Science Publishers, Inc.

Chapter 34

PANITUMUMAB. VECTIBIX®

M. López-Gómez, B. García de Santiago, R. Hernández,


A. M. Jiménez-Gordo and E. Casado
Medical Oncology Department, University Hospital ―
Infanta Sofia,‖ Madrid, Spain

ABSTRACT
Panitumumab is a fully human IgG2 monoclonal antibody directed against the
Epidermal Growth Factor Receptor (EGFR) that inhibits its downstream signalling
pathways (RAS/RAF/MAPK). The protein encoded by this gene is a transmembrane
glycoprotein member of the protein kinase superfamily EGFR. EGFR binds to epidermal
growth factor and this results in a receptor dimerization and tyrosine autophosphorylation
that leads to cell proliferation [1]. Panitumumab prevents the union of EGFR to its ligand,
blocking its downstream pathway and avoiding cell proliferation [2]. Panitumumab is
indicated in metastatic colorectal cancer, either in combination (with FOLFOX or
FOLFIRI) or in monotherapy once the tumor has progressed on previous schedules. Prior
to panitumumab administration RAS mutations must be tested, as they predict a lack of
response to this therapy. Several investigations have shown that tumors with a mutation
in codon 12 or 13 of exon 2 of the KRAS gene are insensitive to panitumumab therapy
[3]. Besides, more recent evidence shows that mutations in KRAS outside of exon 2 and
mutations in NRAS are also predictive for a lack of benefit [4]. Therefore, KRAS and
NRAS genotyping of tumor tissue (either primary tumor or metastasis) should be
performed prior to the administration of this therapy, and patients with known KRAS or
NRAS mutations should not be treated with panitumumab. Testing for BRAF is currently
optional [5].
Panitumumab is administered every 2 weeks and its toxicity manageable, however,
dermatologic toxicities occur in 90% of patients and in 15% are severe (National Cancer
Institute Common Toxicity Criteria [NCI-CTC] grade 3 and higher). Therefore,
appropriate treatment should be started prior to the administration of the therapy.

Keywords: panitumumab, EGFR, KRAS, NRAS


Miriam Lopez-Gomez, e-mail: miriam.lopez@movistar.es.
300 M. López-Gómez, B. García de Santiago, R. Hernández et al.

INTRODUCTION
Panitumumab is a fully human IgG2 monoclonal antibody directed against EGFR that
inhibits its downstream signalling pathways (RAS/RAF/MAPK) [1]. Panitumumab after
binding EGFR blocks the downstream pathway and avoids cell proliferation [2].
Panitumumab is indicated in metastatic colorectal cancer, either in combination (with
FOLFOX or FOLFIRI) or in monotherapy once the tumor has progressed on previous
schedules. Only patients with KRAS and NRAS wild type may benefit from panitumumab.
Currently, testing for BRAF mutations is optional [5].
Although its toxicity is manageable, dermatologic toxicities occur in 90% of patients and
in 15% are severe (National Cancer Institute Common Toxicity Criteria [NCI-CTC] grade 3
and higher). Therefore, appropriate treatment should be started prior to the administration of
the therapy.

CLINICAL PHARMACOLOGY
Drug Classification

Epidermal growth factor receptor antagonist.

Mechanism of Action

The EGFR is a transmembrane glycoprotein that is a member of a subfamily of type I


receptor tyrosine kinases, including EGFR, HER2, HER3, and HER4. EGFR is constitutively
expressed in normal epithelial tissues, including the skin and hair follicle. Besides, EGFR is
over-expressed in certain human cancers, including colon and rectum cancers. Interaction of
EGFR with its normal ligands (e.g., EGF, transforming growth factor-alpha) leads to
phosphorylation and activation of a series of intracellular proteins, which in turn regulate
transcription of genes involved with cellular growth and survival, motility, and proliferation.
However, in cells with activating KRAS somatic mutations, the mutant KRAS protein is
continuously active and appears independent of EGFR regulation.
Panitumumab binds specifically to EGFR on both normal and tumor cells, and
competitively inhibits the binding of ligands for EGFR. This binding of panitumumab to the
EGFR prevents ligand-induced receptor autophosphorylation and activation of receptor-
associated kinases, resulting in inhibition of cell growth, induction of apoptosis, decreased
proinflammatory cytokine and vascular growth factor production, and internalization of the
EGFR. In vitro assays and in vivo animal studies demonstrate that panitumumab inhibits the
growth and survival of selected human tumor cell lines expressing EGFR.
Panitumumab. Vectibix® 301

Pharmacokinetics

Panitumumab administered as a single agent or in combination with chemotherapy


exhibits nonlinear pharmacokinetics.

Absorption Intravenous (iv) administration.


The area under the concentration-time curve (AUC) increases in a greater tan
dose-proportional manner. At doses above 2 mg/kg AUC increases in an
approximately dose-proportional manner and clearance decreasing with
increasing doses.
Distribution Following 6 mg/kg given once every 2 weeks as a 1-hour infusion, panitumumab
concentrations reached steady-state levels by the third infusion with mean (± SD)
peak and trough concentrations of 213 ± 59 and 39 ± 14 mcg/mL, respectively.
Human IgG crosses the placenta and is distributed into milk. There is a potential
risk that panitumumab crosses the placenta and possibly distributed into milk.
Low levels cross brain barrier
Metabolism It is not completely understood.
Elimination The elimination half-life is approximately 7.5 days (range 3.6 to 10.9 days)
Systemic clearance is believed to be through internalization of panitumumab-
EGFR complex and via the reticuloendothelial system.

Results suggest that age (21-88 years), gender, race (15% non-white), mild-to-moderate
renal dysfunction, mild-to-moderate hepatic dysfunction, and EGFR membrane-staining
intensity (1+, 2+, 3+) in tumor cells had no apparent impact on the pharmacokinetics of
panitumumab.

Mechanism of Resistance

Panitumumab is not indicated for treatment of RAS mutation positive colorectal cancer.

Indications

Panitumumab is indicated for the treatment of metastatic colorectal cancer in patients


with KRAS exon 2 and RAS wild-type metastatic colorectal cancer the following situations:

 In first and second line setting in combination with FOLFOX (5 Fluorouracil,


leucovorin and oxaliplatin) therapy.
 In first and second line setting in combination with FOLFIRI (5 Fluorouracil,
leucovorin and irinotecan) therapy (used in second line in those patients who haven‘t
receiven irinotecan as part of first line treatment).
 In third line setting in monotherapy after progression to oxaliplatin and irinotecan
schedules.
302 M. López-Gómez, B. García de Santiago, R. Hernández et al.

Dosages

The recommended dose of Panitumumab is 6 mg/kg, administered as an iv infusion over


60 minutes, every 14 days. Doses higher than 1000 mg should be administered over 90
minutes.
Dosages forms and strengths are:

 single-use vials (20 mgr/ml): 100 mgr/5 ml, 200 mgr/10 ml and 400 mgr/20 ml.

Methods of Preparation/Administration

The solution for infusion should be prepared using an aseptic technique:

1. It should be inspected visually for particulate matter and discoloration prior to


administration. It should‘t be shaked.
2. The necessary amount of Panitumumab should be withdrawn for a dose of 6 mg/kg.
3. A total volume of 100 ml should be diluted with 0.9% sodium chloride injection, and
except for doses higher than 1000 mg which should be diluted to 150 mL with 0.9%
sodium chloride injection.

To be administered:

1. It should be administered using a low-protein-binding 0.2 μm or 0.22 μm in-line


filter, via infusion pump.
2. Line should be flushed before and after Panitumumab administration with 0.9%
sodium chloride injection.
3. It must never be mixed with other medicinal products.
4. It should be infused over 60 minutes through a peripheral iv line or indwelling iv
catheter.
5. Doses higher than 1000 mg should be infused over 90 minutes. The diluted infusion
solution of Panitumumab should be used within 6 hours of preparation if stored at
room temperature, or within 24 hours of dilution if stored at 2° to 8°C (36° to 46°F).
It must never be frozen.

Special Information and Cautions

Contraindications
None.

Elderly
Apparently there are not differences in safety and effectiveness between these and
younger patients.
Panitumumab. Vectibix® 303

Pediatric
The safety and effectiveness of panitumumab have not been established in pediatric
patients.

Renal Impairment
The safety and efficacy of panitumumab have not been studied in renal impairment.
Acute renal failure has been observed in patients experiencing severe diarrhea and
dehydration.

Hepatic Impairment
The pharmacokinetics in patients with hepatic impairment has not been investigated, and
dosage adjustments are undetermined.

Immunisations
Live vaccines should not be applied while taking the treatment or for at least 6 months
afterwards. Other vaccines can be administered, though may not give as much protection as
usual. In any case, it is safe to be in contact with other people who have had live vaccines as
injections. There can be problems with oral vaccines. Any contacts with someone who has
had oral polio, cholera or typhoid vaccination recently, should be avoided.

Pregnancy
It may cause fetal harm. Pregnancy should be avoided while on the treatment.

Lactation
IgG distributed into human milk. Panitumumab or breast-feeding should be discontinued.
If breast-feeding is interrupted, based on the mean half-life of panitumumab, nursing should
not be resumed earlier than 2 months following the last dose of panitumumab.

Warnings

Infusion Reactions
In case of infusion reactions infusion rate should be reduced by 50% for mild reactions
and should be immediately and permanently discontinued for severe reactions.

Electrolyte Depletion/Monitoring
Hypomagnesemia occurs 6 weeks or longer after the initiation of panitumumab, and
patients‘ electrolytes should be periodically monitored during and for 8 weeks after the
completion of panitumumab therapy. In some patients, both hypomagnesemia and
hypocalcemia occur. Oral or iv electrolyte repletion must be corrected.

Photosensitivity
Exposure to sunlight can exacerbate dermatologic toxicity secondary to panitumumab
therapy. Patients should be advised to wear sunscreen and hats and limit sun exposure while
receiving panitumumab.
304 M. López-Gómez, B. García de Santiago, R. Hernández et al.

Dermatology Toxicity
Treatment of skin rash might include topical clyndamicin 2% plus hydrocortisonse 1% in
mild pustular or papular eruption.
In the case of moderate pustular, papular eruption or erythema doxyciline 100 mgr once
daily should be added for minimum 4 weeks and continuing for the duration of treatment.
In severe, extensive, painful and intolerate rash treatment with panitumumab should be
discontinued.

Toxicities

System Organ Class Very Common ≥1/10 Common ≥1/1000 to <1/10 Uncommon Rare (≥1/10.000
≥1/1,000 to a <1/1.000)
<1/1000
Blood and lymphatic Hypokalemia, Leukopenia,
hypomagnesaemia hypocalcaemia,
dehydration,
hyperglycemia,
hypophosphatemia.
Cardiovascular Tachycardia, deep venous
disorders thrombosis, hypo/
hypertension, flush, chest
pain, pulmonary embolism
Respiratory Disnea, cough Epistaxis Cyanosis,
bronchoespasm,
nasal dryness
Eye Conjunctivitis, Conjunctival hyperaemia, Eye infection, Ulcerous
xerophthalmia, itchy watery keratitis, eyelid keratitis
eyes, blepharitis, eyelash infection
growth, increased tear-
shedding
Nervous System Anxiety, dizziness
Gastrointestinal Diarrhea, nausea, Rectal bleeding, dry mouth,
vomiting, abdominal dyspepsia, aphthous
pain, stomatitis, stomatitis
constipation, Cheilitis, Gastroesophageal
Reflux Disease,
Immunological Hypersensitivity Angioedema Anaphylactic
disorders shock, Stevens-
Johnson
syndrome
Skin and nail Paronychia, dermatitis, Pustular eruption, cellulitis, Onycholysis
disorders erythema, dry skin, folliculitis, located
alopecia, acneiform infection, palmoplantar
rash erythrodysesthesia
syndrome, cutaneous ulcer,
hypertrichosis, nail
disorders, hypertrichosis
General Insomnia, asthenia,
weight loss, peripheral
edema, mucosae
inflammation
Musculoskeletal Back pain Extremities pain
disorders
Frequency unknown
Interstitial lung disease
Panitumumab. Vectibix® 305

Dose Modifications

1. For Infusion Reactions


Infusion rate should be reduced by 50% in patients experiencing a mild or moderate
(grade 1 or 2) infusion reaction for the duration of that infusion. It should be immediately and
permanently discontinued in patients experiencing severe (grade 3 or 4) infusion reactions.

2. Dermatologic Toxicity
Panitumumab treatment should be withheld for dermatologic toxicities that are grade 3 or
higher or are considered intolerable.
Manage of dermatologic toxicity should be as follows:

 Grade 3 toxicity (first occurrence): Panitumumab should be withheld 1 to 2 doses; if


reaction improves to <grade 3, it should be resumed at initial dose.
 Grade 3 toxicity (second occurrence): Panitumumab should be withheld 1 to 2 doses;
if reaction improves to <grade 3, it should be resumed at 80% of initial dose.
 Grade 3 toxicity (third occurrence): Panitumumab should be withheld 1 to 2 doses; if
reaction improves to <grade 3, it should be resumed at 60% of initial dose.
 Grade 3 toxicity (fourth occurrence) that does not recover to <grade 3 after
withholding 1 or 2 doses, or grade 4 toxicity: Panitumumab should be permanently
discontinued.

3. Ocular or Pulmonary Toxicity


Panitumumab should be permantently discontinued.

Interactions

No formal drug-drug interaction studies have been conducted with Vectibix.

CONCLUSION
Panitumumab is an antibody directed against EGFR indicated in the treatment of mCRC
in first and second line (either in combination with FOLFOX or with FOLFIRI) or in third
line as a single drug.
The blockade of the ligand to its receptor results in an inhibition of cell proliferation.
Determination of mutation status of KRAS and NRAS is mandatory prior to panitumumab
administration as its used in patients with KRAS/NRAS mutation-positive mCRC is
detrimental. It is administered iv every 2 weeks and its toxicity is manageable, being the most
frequent secondary events dermatologic toxicity, diarrhea and electrolyte depletion. The
presence and severity of skin rash toxicity has been shown to predict increased response and
survival in patients treated with anti-EGFR therapy, and can be used as a predictive marker of
this therapy. Early treatment of skin rash should be initiated in these patients.
306 M. López-Gómez, B. García de Santiago, R. Hernández et al.

REFERENCES
[1] Chakraborty S, Li L, Puliyappadamba VT, Guo G, Hatanpaa KJ, Mickey B et al.
Constitutive and ligand-induced EGFR signalling triggers distinct and mutually
exclusive downstream signalling networks. Nat Commun 2014;5:5811.
[2] Messersmith W.A, and Hidalgo M. Panitumumab, a monoclonal antiepidermal growth
factor receptor antibody in colorectal cancer: another one or the one? Clin Cancer Res
13(16):4664-6.
[3] Amado RG, Wolf M, Peeters M, Van Cutsem E, Siena S, Freeman DJ et al. Wild type
KRAS is required for panitumumab efficacy in patients with metastatic colorectal
cancer. J. Clin Oncol 2008;26: 1626-1634.
[4] Douillard JY, Oliner KS, Siena S, Tabernero J, Burkes R, Barugel M et al.
Panitumumab-Folfox 4 treatment and RAS mutations in colorectal cancer: a
metanalyses of randomized controlled trials. Ann Oncol 2014.
[5] Rowland A, Dias MM, Wiese MD, Kichenadasse G, Mc Kinnon RA, Karapetis CS.
Meta-analysis of BRAF mutation as a predictive biomarker of benefit from anti-EGFR
monoclonal antibody therapy for RAS wild-type metastatic colorectal cancer. Br J
Cancer, 2015 doi: 10.1038/bjc.2015.173 [Epub. ahead of print].
In: The Easy Book of Cancer Pharmacology ISBN: 978-1-63485-038-4
Editor: Esther Una Cidon © 2016 Nova Science Publishers, Inc.

Chapter 35

PAZOPANIB. VOTRIENT®

A. Hernandez-Sanchez
Pharmacy Department, Royal Bournemouth
and Christchurch Hospitals NHS Foundation Trust

ABSTRACT
Pazopanib hydrochloride is an antineoplastic agent, inhibitor of multiple receptor
tyrosine kinases, approved by the US Food and Drug Administration (FDA) in October
2009 and the European Medicines Agency (EMA) in June 2010. Pazopanib is licensed
for the treatment in adults of advanced renal cell carcinoma (RCC) in first line and for
patients who have received prior cytokine therapy at a dose of 800mg once a day [1]. In
2012 FDA approved pazopanib hydrochloride tablets for the treatment of advanced soft
tissue sarcoma (STS) who have received prior chemotherapy [2].
Those indications are based principally on the results of a randomized phase III
trials, showing significantly prolonged PFS against placebo [3, 4].
In RCC, a large non-inferiority study showed similar efficacy to sunitinib and safer
profile. The tablets should be taken as a whole and without food. Pazopanib is
incompletely absorbed from the gastrointestinal (GI) system, and peak plasma
concentrations occur at a median of 2–4 hours. Pazopanib is principally metabolised by
the hepatic isoenzyme CYP3A4, and its levels are subject to inhibitors and inducers of
this enzyme. Adequate patient evaluation and monitoring include liver function tests,
ECG, electrolytes, blood pressure, thyroid function and urinalysis prior to initiation of
pazopanib and periodically during therapy. The most frequent adverse events related to
pazopanib treatment were diarrhoea, hair colour change, hypertension, taste disturbance,
nausea, anorexia and increased liver enzymes.

Keywords: pazopanib, renal cell carcinoma


Email: Alfredo.hernandez-sanchez@rbch.nhs.uk.
308 A. Hernandez-Sanchez

INTRODUCTION
Pazopanib is an oral angiogenesis inhibitor targeting vascular endothelial growth factor
receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), and stem cell growth
factor receptor (c-Kit), licensed for the treatment in adults for the first line treatment of
advanced RCC and for patients who have received prior cytokine therapy for advanced
disease at a dose of 800mg once a day. It is also indicated for advanced STS who progressed
with prior chemotherapy. It presents as modified capsule-shaped and film-coated tablets
containing either 200 or 400mg of pazopanib.

CLINICAL PHARMACOLOGY
Drug Classification

Pazopanib hydrochloride is an oral antineoplastic agent, inhibitor of multiple receptor


tyrosine kinases [1].

Mechanism of Action

Pazopanib is an oral angiogenesis inhibitor targeting VEGFR (VEGFR)-1, -2, and -3,
PDGFR-α and –β, and c-KIT [1].

Pharmacokinetics [1]

Absorption Median Tmax 2-4 hours-1


AUC 1,037 hr•μg/mL
Cmax 58.1 μg/mL
Distribution Binding to plasma protein > 99%
Metabolism CYP3A4 (also CYP1A2 and CYP2C8)
Excretion Half-life 30.9h
Faeces
<4% urine

INDICATIONS [1]
Pazopanib is indicated for the treatment in adults for the first line treatment of advanced
RCC and for patients who have received prior cytokine therapy for advanced disease.
It is also indicated for the treatment of adult patients with selective subtypes of advanced
STS who have received prior chemotherapy for metastatic disease or who have progressed
within 12 months after (neo) adjuvant therapy. Efficacy and safety has only been established
in certain STS histological tumour subtypes.
Pazopanib. Votrient® 309

Pazopanib eye drops are under investigation for the treatment of age-related macular
degeneration.

DOSAGE [1]
The recommended dose of pazopanib for the treatment of RCC or STS is 800 mg orally
once daily.

METHODS OF ADMINISTRATION/PREPARATION [1]


Pazopanib should be taken orally without food, at least one hour before or two hours after
a meal, as the rate of absorption and systemic exposure to pazopanib are increased when
administered with food.
The tablets should be swallowed as a whole with water and not broken or crushed, since
it could potentially increase the rate of absorption which many affect systemic exposure.

SPECIAL INFORMATION AND CAUTIONS [1]


Contraindications

Hypersensitivity to the active substance or to the excipients which are listed below:
List of excipients

 Tablet core
- Magnesium stearate
- Microcrystalline cellulose
- Povidone (K30)
- Sodium starch glycolate (type A)

 Film-coated
- Hypromellose
- Red iron oxide (E172)
- Macrogol 400
- Polysorbate 80
- Titanium dioxide (E171)

Elderly Patient

There is limited data in patients aged 65 years and older. No clinically significant
differences in safety of pazopanib have been observed, but greater sensitivity of some older
individuals cannot be ruled out.
310 A. Hernandez-Sanchez

Pediatric Patients

Pazopanib should not be used in children younger than 2 years of age. The safety and
efficacy of pazopanib in children aged 2 to 18 years of age have not yet been established.

Renal Impairment

Dose adjustment is not required in patients with creatinine clearance above 30 ml/min.
Caution is advised in patients with creatinine clearance below 30 ml/min as there is no
experience of pazopanib in this patient population.

Hepatic Impairment

Hepatotoxicity, manifested as increased in serum transaminases (ALT, AST) and


bilirubin has been observed. It can be severe and fatal. Administration of pazopanib to
patients with mild or moderate hepatic impairment should be undertaken with caution and
close monitoring. Pazopanib is contraindicated in patients with severe hepatic impairment.
All patients should have liver function tests before initiation of treatment with pazopanib and
at weeks 3, 5, 7 and 9. Thereafter, monitored at month 3 and at month 4, and as clinically
indicated. Periodic monitoring should then continue after month 4.

Fertility

Animal studies indicate that male and female fertility may be affected by treatment with
pazopanib.

Pregnancy (Category D)

Pazopanib can cause foetal harm when administered to a pregnant woman. Women of
childbearing potential should be advised to avoid becoming pregnant while taking pazopanib.
If this drug is used during pregnancy, or if the patient becomes pregnant while taking this
drug, the patient should be apprised of the potential hazard to the foetus.

Breast-Feeding

The safe use of pazopanib during lactation has not been established. It is not known
whether pazopanib is excreted in human milk. A risk to the suckling child cannot be
excluded. Breast-feeding should be discontinued during treatment with pazopanib.
Pazopanib. Votrient® 311

WARNINGS [1]
 Pazopanib should not be used in patients with a history of haemoptysis, cerebral or
clinically significant GI haemorrhage. Pazopanib should be used with caution in
patient with significant risk of haemorrhage. Monitoring for GI perforation and
fistulae is recommended.
 Prolonged QT intervals and torsades de pointes have been observed. Pazopanib
should be used with caution in patients with a history of QT interval prolongation, in
patients taking antiarrhythmics or other medications that may prolong QT interval,
and those with relevant pre-existing cardiac disease. Electrocardiograms should be
monitored prior to initiation of pazopanib and periodically during treatment; serum
electrolytes (e.g., calcium, magnesium, potassium) within normal range is
recommended.
 Pazopanib should be used with caution in patients who are at increased risk for
myocardial infarction, angina, ischemic stroke and transient ischemic attack. It
should not be used in patients who have had an event within the previous 6 months.
 Blood pressure should be well-controlled prior to initiating pazopanib. Patients
should be monitored for hypertension, early after starting treatment (no longer than
one week after starting pazopanib) and frequently thereafter. Hypertension should be
managed promptly using a combination of anti-hypertensive therapy and dose may
be reduced. Pazopanib should be discontinued if hypertension is severe and persistent
despite anti-hypertensive therapy and dose reduction of pazopanib.
 Since pazopanib may impair wound healing, it should be stopped at least 7 days prior
to scheduled surgery. The decision to resume it after surgery should be based on
clinical judgment of adequate wound healing. Pazopanib should be discontinued in
patients with wound dehiscence.
 Hypothyroidism has been reported as an adverse reaction. Baseline laboratory
measurement of thyroid function is recommended and patients with hypothyroidism
should be treated as per standard medical practice prior to the start of pazopanib
treatment. All patients should be observed closely for signs and symptoms of thyroid
dysfunction on pazopanib treatment. Laboratory monitoring of thyroid function
should be performed periodically.
 Proteinuria has been reported. Baseline and periodic urinalysis during treatment is
recommended. Pazopanib should be discontinued if the patient develops nephrotic
syndrome.
 Patients on pazopanib treatment should be observed closely for signs and symptoms
of pneumothorax.
 Posterior reversible encephalopathy syndrome (PRES)/Reversible posterior
leukoencephalopathy syndrome (RPLS)

PRES/RPLS can present with headache, hypertension, seizure, lethargy, confusion,


blindness and other visual and neurological disturbances, and can be fatal. It has been
reported in association with pazopanib. Patients developing PRES/RPLS should permanently
discontinue treatment with pazopanib.
312 A. Hernandez-Sanchez

TOXICITIES [1]
System organ Very common Common Uncommon Rare
class (≥ 1/10) (≥1/100 to <1/10) (≥1/1000 to <1/100) (≥1/10,000 and
<1/1000)
Vascular Hypertension Flushing, Venous Hypertensive crisis,
disorders Thromboembolic event blood pressure diastolic
increased,
blood pressure systolic
increased
ENT disorders Ear, nose and throat Mouth haemorrhage,
examination abnormal, oropharyngeal pain,
Epistaxis, mouth ulceration rhinorrhoea
Skin, hair and Alopecia, hair Skin depigmentation; skin Plantar erythema, nail
subcutaneous colour change, hypopigmentation, disorders, skin exfoliation,
tissue disorders palmar-plantar erythema, hyperhidrosis skin ulcer
erythrodysaesthesia Rash: erythematous, macular,
syndrome, rash papular, pruritic, vesicular
Infections and Infections (with/without
infestation neutropenia, infectious
disorders peritonitis, gingival infection
Musculoskeletal Arthralgia, muscle spasms, Musculoskeletal pain
disorders myalgia
Metabolism and Decreased appetite, Dehydration, weight
nutrition diarrhoea, decreased, dry skin
disorders dysgeusia
Nervous system Headache Paraesthesia, peripheral Hypoesthesia, paresthesia, PRES/RPLS
disorders sensory neuropathy, ischaemic stroke, transient
lethargy, dizziness, ischaemic attack, somnolence,
insomnia
Cardiac Bradycardia, chest pain, left myocardial ischaemia,
disorders ventricular dysfunction myocardial infarction, QT
prolonged,
bradycardia, cardiac
dysfunction
Gastrointestinal Nausea, vomiting Stomatitis, Peritonitis, pancreatitis,
disorders abdominal distension, dry frequent bowel movements
mouth, GI haemorrhage: oesophageal
dyspepsia, flatulence, haemorrhage, haematemesis,
hiccups haematochezia, melenas,
rectal, anal or haemorrhoidal
haemorrhage
Perforation: ileal or large
intestine perforation. Fistula:
Enterocutaneous fistula
Hepatobiliary Alanine Hyperbilirubinaemia, Increased ALT and AST,
disorders aminotransferase hepatotoxicity, GGT jaundice, hepatic failure
increased, increased
Aspartate
aminotransferase
increased
Respiratory, Cough, dysphonia, Pneumothorax
thoracic and dyspnoea, haemoptysis Haemorrhage: bronchial,
mediastinal pulmonary
disorders
Endocrine Thyroid stimulating
disorders hormone, hypothyroidism,
hot flush, thyroid function
test abnormal
Renal and Proteinuria Haemorrhage urinary tract
urinary
disorders
Pazopanib. Votrient® 313

System organ Very common Common Uncommon Rare


class (≥ 1/10) (≥1/100 to <1/10) (≥1/1000 to <1/100) (≥1/10,000 and
<1/1000)
General Abdominal pain, Asthenia, oedema, chills, Photosensitivity reaction, Thrombotic
disorders and fatigue pruritus, mucosal chills, retroperitoneal microangiopathy
administration inflammation haemorrhage (including
site conditions thrombotic
thrombocytopenic
purpura and
haemolytic
uraemic
syndrome)
Investigations High levels amylase, Hypomagnesaemia,
cholesterol, creatinine, urea, hypoglycemia
lipase,
Hypophosphataemia,
Blood and Leukopenia, neutropenia,
lymphatic thrombocytopenia
disorders
Eye disorders Vision blurred Eyelash discolouration,
Retinal:
detachment, tear
Gynaecological Menorrhagia, metrorrhagia,
disorders vaginal haemorrhage
Tumor Tumor pain
disorders

DOSE MODIFICATIONS [1]


Dose modification should be in steps of 200 mg increments in a stepwise fashion based
on individual tolerability in order to manage adverse reactions. The dose of pazopanib should
not exceed 800 mg.

Transaminases Bilirubin Dosage Transaminases Bilirubin Dosage


< 1.5 x ULN Full dose < 1.5 ULN Full dose
> 1.5 - 3 x 200 mg daily
ULN
> 3 ULN Not
recommended
>3 x ULN Mild, Continue with weekly >3 x ULN > 2 ULN Stopped
unconjugated monitoring until grade 1 permanently
with Gilbert or baseline
Syndrome
3 - 8 x ULN Continue with weekly
monitoring until grade 1
or baseline
>8 x ULN Stop it until grade 1 or
baseline*
*
If the benefit outweighs risk, pazopanib can be restarted at a dose of 400mg or less once daily and liver function
monitored weekly for 8 weeks. Following reinitiation, if transaminase elevations >3 x ULN recur, then pazopanib
should be permanently discontinued.

Other Dose Modifications

See Warnings section.


314 A. Hernandez-Sanchez

INTERACTIONS [1]
Pazopanib is metabolised primarily by CYP3A4, with minor contributions from CYP1A2
and CYP2C8.
CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir,
indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole, lapatinib,
grapefruit juice) may increase pazopanib concentrations. Concomitant use of pazopanib with
a strong CYP3A4 inhibitor should be avoided. If no medically acceptable alternative to a
strong CYP34A inhibitor is available, the dose of pazopanib should be reduced to 400 mg
daily during concomitant administration. In such cases there should be close attention to
adverse drug reaction, and further dose reduction may be considered if possible drug-related
adverse events are observed.
CYP3A4 inducers (e.g., rifampicin) may decrease plasma pazopanib concentrations.
Concomitant use of pazopanib with a potent inducer of CYP3A4 should be avoided, and
selection of an alternative agent with minimal or no enzyme induction potential should be
considered. If chronic use of a potent CYP3A4 inducer is required, pazopanib should not be
initiated.

Combination with Other Systemic Anti-Cancer Therapies

Clinical trials of pazopanib in combination with pemetrexed (non-small cell lung cancer
(NSCLC)) and lapatinib (cervical cancer) were terminated early due to concerns over
increased toxicity and/or mortality, and a safe and effective combination dose has not been
established with these regimens.

Effect of Pazopanib on Other Drugs

Pazopanib increases the levels of midazolam and paclitaxel, and the ratio of
dextrometorphan to dextrophan concentrations in the urine after oral administration of
dextromethorphan. Co-administration of pazopanib with cetuximab and irinotecan resulted in
an increase in systemic exposure to SN-38, the active metabolite of irinotecan.
Concomitant use of pazopanib and simvastatin increases the incidence of ALT elevations.
It cannot be excluded that pazopanib will affect the pharmacokinetics of other statins.
Concomitant administration of pazopanib with esomeprazole decreases the bioavailability
of pazopanib. Co-administration of pazopanib with medicines that increase gastric pH should
be avoided. If the use of a proton-pump inhibitor (PPI) is medically necessary, it is
recommended that the dose of pazopanib be taken without food once daily in the evening
concomitantly with the PPI. If the concomitant administration of an H2-receptor antagonist is
medically necessary, pazopanib should be taken without food at least 2 hours before or at
least 10 hours after a dose of an H2-receptor antagonist. Pazopanib should be administered at
least 1 hour before or 2 hours after administration of short-acting antacids.
Pazopanib. Votrient® 315

CONCLUSION
Pazopanib is an oral angiogenesis inhibitor targeting VEGFR-1, -2, and -3, PDGFR-α and
–β, and c-KIT, licensed for the treatment in adults of RCC in first line and for patients who
have received prior cytokine therapy and STS who have received prior chemotherapy. These
indications are based principally on the results of a randomized phase III trials, showing
significantly prolonged PFS against placebo [1].
Pazopanib is principally metabolised by the hepatic isoenzyme CYP3A4, and its levels
are subject to inhibitors and inducers of this enzyme. Adequate patient evaluation and
monitoring include liver function tests, ECG, electrolytes, blood pressure, thyroid function
and urinalysis prior to initiation of pazopanib and periodically during therapy. The most
frequent adverse events related to pazopanib treatment were diarrhoea, hair colour change,
hypertension, taste disturbance, nausea, anorexia and increased liver enzymes [1].

REFERENCES
[1] European Medicines Agency, 2014. Pazopanib. Summary of Product Characteristics.
https://www.medicines.org.uk/emc/print-document? documentId=23148 (accessed May
2015).
[2] Pazopanib. http://www.cancer.gov/about-cancer/treatment/drugs/fda-pazopanibhydro
chloride.
[3] Sternberg CN, Hawkins RE, Wagstaff J, Salman P, Mardiak J, Barrios CH, Zarba JJ,
Gladkov OA, Lee E, Szczylik C, McCann L, Rubin SD, Chen M, Davis ID. A
randomised, double-blind phase III study of pazopanib in patients with advanced and/or
metastatic renal cell carcinoma: final overall survival results and safety update. Eur J
Cancer. 2013;49(6):1287-96.
[4] van der Graaf WT, Blay JY, Chawla SP, Kim DW, Bui-Nguyen B, Casali PG,
Schöffski P, Aglietta M, Staddon AP, Beppu Y, Le Cesne A, Gelderblom H, Judson IR,
Araki N, Ouali M, Marreaud S, Hodge R, Dewji MR, Coens C, Demetri GD, Fletcher
CD, Dei Tos AP, Hohenberger P; EORTC Soft Tissue and Bone Sarcoma Group;
PALETTE study group. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a
randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2012;379
(9829):1879-86.
[5] US Food and Drug Administration. Highlights of prescribing information: VOTRIENT.
http://www.accessdata.fda.gov/drugsatfda_ docs/label/2009/022465lbl.pdf (accessed
May 2015).
[6] Escudier B, Porta C, Schmidinger M, Algaba F, Patard JJ, Khoo V, et al. Renal cell
carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
Annals Of Oncology 2014:iii49–iii56.
[7] NCCN Clinical practice guidelines in oncology. Kidney Cancer. Version 3.2015.
http://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf (accessed February
2015).
316 A. Hernandez-Sanchez

[8] Griffiths C, Hay N, Sutcliffe F, Stevens A. NICE guidance on pazopanib for first-line
treatment of advanced renal-cell carcinoma. The Lancet Oncology 2011:221–2.
[9] Pazopanib: AHFS Drug Information. https://www.medicinescomplete. com/mc/ahfs/
current/a310010.htm?q=pazopanib&t=search&ss=text&p=1#_hit (accessed May 2015).
In: The Easy Book of Cancer Pharmacology ISBN: 978-1-63485-038-4
Editor: Esther Una Cidon © 2016 Nova Science Publishers, Inc.

Chapter 36

PEMBROLIZUMAB. KEYTRUDA®

E. Una Cidon
Medical Oncology Department, Royal Bournemouth Hospital NHS Foundation Trust,
Bournemouth, UK

ABSTRACT
Pembrolizumab is a monoclonal antibody that binds to the programmed cell death-1
protein (PD-1) receptor and blocks interaction with its ligands, programmed death ligands
(PD-L1 and PD-L2). This activates T-cell–mediated immune responses against tumour
cells. The US Food and Drug Administration (FDA) approved pembrolizumab for the
treatment of patients with unresectable or metastatic melanoma who had disease
progression after receiving ipilimumab and a BRAF inhibitor if BRAF V600 mutation. It
has also been approved for metastatic squamous and non-squamous non-small cell lung
cancer (NSCLC) [1-4].

Keywords: pembrolizumab, PD-1, PD-L1, PD-L2, monoclonal antibody

INTRODUCTION
Pembrolizumab is a monoclonal antibody that binds to the programmed cell death-1
protein (PD-1) receptor and blocks interaction with its ligands, programmed death ligands
(PD-L1 and PD-L2). This activates T-cell–mediated immune responses against tumour cells.
FDA approved it for the treatment of unresectable or metastatic melanoma after progression
on ipilimumab and a BRAF inhibitor if BRAF V600 mutation and also in metastatic NSCLC
across all histologies and tumours which express PD-L1, after progression on or after
platinum-containing chemotherapy, as well as a targeted agent in epidermal growth factor
receptor– or anaplastic lymphoma kinase–positive patients. Pembrolizumab is now the second
FDA-approved PD-1 inhibitor in lung cancer and the first across all NSCLC histologies [1-4].


Esther Una Cidon. aunacid@hotmail.com; esther.unacidon@rbch.nhs.uk.
318 E. Una Cidon

CLINICAL PHARMACOLOGY [5-7]


Drug Type

Antineoplastic agent, monoclonal antibody.

Mechanism of Action

It binds to PD-1 receptor and blocks the interaction between PD-1 and its ligands PD-L1
and PD-L2.
In some tumours, PD-1 ligands are upregulated and signalling through this pathway
inhibits the active T-cell surveillance of tumours.
Pembrolizumab binds to the PD-1 receptor and releases PD-1 pathway-mediated
inhibition of the immune response, including the antitumor immune response.

Indications

Melanoma
Unresectable or metastatic melanoma and disease progression following ipilimumab and,
if BRAF V600 mutation positive, a BRAF inhibitor.

Pharmacokinetics

Absorption Intravenous (iv) administration


Bioavailability 100%
Distribution Limited extravascular distribution.
Not expected to bind to plasma proteins.
Volume of distribution at steady state is ~7.7L.
Metabolism Metabolised through non-specific pathways.
Metabolism does not contribute to its clearance.
Excretion Clearance is 0.22 L/day
Half-life is 26 days
Steady-state concentration reached by 18 weeks of 3 weekly dosing.

Non-Small Cell Lung Cancer (NSCLC)


Accelerated approval.
Metastatic NSCLC in patients whose tumours express PD-L1 with disease progression on
or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumour
aberrations should have disease progression on therapy for these aberrations prior to receiving
pembrolizumab.
Pembrolizumab. Keytruda® 319

Gastric and Gastroesophageal Junction Adenocarcinomas

Orphan designation for the treatment of these tumours.

Dosage

Administer 2 mg/kg every 3 weeks.

Methods of Preparation/Administration

Add 2.3 mL of sterile water by injecting it along the walls of the vial. Slowly swirl the
vial, do not shake it and allow for the bubbles to clear.
Visually inspect the solution for particulates and discoloration. Reconstituted solution is a
clear to slightly opalescent, colourless to slightly yellow. Discard it if extraneous particulate
matter other than translucent to white proteinaceous particles is observed.
Withdraw the required volume from the vial and transfer into an iv bag containing 0.9%
Sodium Chloride. Mix diluted solution by gentle inversion. Final concentration should be
between 1-10 mg/mL.
Discard any unused portion left.
This product does not contain a preservative and it should be stored either at room
temperature for no more than 4 hours from the time of reconstitution including duration of
infusion. Or under refrigeration at 2- 8°C for no more than 24 hours. If refrigerated, solution
should come to room temperature before administration. Do not freeze.

Administration

Iv infusion over 30 minutes.


Through an iv line with a sterile, non-pyrogenic, low-protein binding 0.2-5 micron in-line
or add-on filter.
Do not co-administer other drugs through the same infusion line.

SPECIAL INFORMATIONS AND CAUTIONS [5-7]


Contraindications

-Hypersensitivity to the active drug or to its excipients listed below:

L-histidine
L-histidine hydrochloride monohydrate
Saccharose
Polysorbate 80
320 E. Una Cidon

Elderly

Dose adjustment is not needed.

Pediatric

It is not established safety or efficacy in this population.

Renal Impairment

Safety and efficacy has not been studied in severe renal impairment but no dose
adjustment is needed if mild to moderate renal impairment.

Hepatic Impairment

If mild hepatic impairment no dose adjustment is needed. Not studied in patients with
moderate or severe.

Hepatic impairment Total bilirubin AST Dosage


MILD Less than or equal to AST greater than No dose adjustment
upper limit normal ULN
(ULN)
1-1.5 x ULN Any
MODERATE >1.5-3 x ULN Any Not studied
SEVERE > 3 x ULN

Immunisations

Live vaccines should not be applied while taking the treatment or for at least 6 months
afterwards. Other vaccines can be administered, though may not give as much protection as
usual. In any case, it is safe to be in contact with other people who have had live vaccines as
injections. There can be problems with oral vaccines. Any contacts with someone who has
had oral polio, cholera or typhoid vaccination recently, should be avoided.

Pregnancy

It may cause fetal harm. Therefore, highly effective contraception should be used during
treatment and for at least 4 months following the last dose of pembrolizumab.
Pembrolizumab. Keytruda® 321

Breast-Feeding

Unknown if it is excreted in maternal milk, but due to the potential adverse effects in the
baby, it is advisable to stop nursing while on the treatment.

Warnings

Immune-Mediated Adverse Reactions


Monitor for changes in liver enzymes, renal function, thyroid enzymes, symptoms and
signs of hypophysitis, etc. See dose modifications section.

Pneumonitis
Colitis
Hepatitis
Hypophysitis
Nephritis
Hyperthyroidism/hypothyroidism

Toxicity [7]

Organic system Very Common ≥ 1/1000 to Uncommon Rare (≥ 1/10.000 a <


disorders Common < 1/10 ≥ 1/1,000 to <1/1000 1/1.000)
≥ 1/10
Infections and Pneumonia, conjunctivitis,
Infestations shingles, candidiasis,
disorders diverticulitis, influenza,
UTI, oral herpes,
folliculitis, nasopharyngitis
Related to the Tumour pain Acrochordon, tumour
cancer growing
Immunological Autoimmune
disorders diseases
Endocrine Hypophysitis, Thyroiditis, adrenal
disorders hyperthyroidism, insufficiency
hypothyroidism
Nervous system Headache, peripheral Confusion, insomnia, Agitation,
and psychiatric neuropathy, hypersomnia, anxiety, hallucinations,
disorders dizziness, depression, decreased trance, affective
paresthesias, taste libido, hypoesthesia, disorders, brain
disturbances hyperesthesia, lethargy, oedema,
neuralgia, sensitive encephalopathy,
peripheral neuropathy, taste epilepsy, non-
reduction, hypotonia, infective meningitis,
memory reduction, seizures, syncope,
unsteadiness, tremor, partial crisis,
attention deficit, restless dysarthria,
legs myasthenic syndrome
322 E. Una Cidon

(Continued)

Organic system Very Common ≥ 1/1000 Uncommon Rare (≥ 1/10.000 a <


disorders Common to < 1/10 ≥ 1/1,000 to <1/1000 1/1.000)
≥ 1/10
Blood and Anaemia, Neutropenia, Pancytopenia,
lymphatic thrombocytopenia lymphopenia, haemolytic anaemia,
system disorders eosinophilia, leucopenia immune
thrombocytopenic
purpura
Eye and ENT Dry eye, vertigo Uveitis, ocular pain, Diplopia, photopsia,
disorders itchiness, irritation, macular degeneration,
photophobia, blurry periorbital oedema,
vision, lacrimation, positional vertigo
hyperemia, eyelashes
discolouration, vitreous
floating cells, epistaxis,
rhinorrhea
Renal and urinary Nephritis, acute and Urinary incontinence
disorders chronic renal failure,
polyuria, dysuria
Respiratory, Pneumonitis, Pleuritic pain, dysphonia, Pleural effusion,
thoracic dyspnea, cough nasal congestion, respiratory airways
and mediastinal oropharyngeal pain, congestion
disorders haemoptisis, productive
cough, wheezing, painful
respiration, sneezing
Gastrointestinal Nauseas, Colitis, vomiting, Pancreatitis, dysphagia, Small bowel
disorders diarrhoea abdominal pain, dry oral pain, perforation, upper
mouth, constipation, gastroesophageal reflux, gastrointestinal
abdominal distention dyspepsia, gastritis, haemorrhage,
haemorrhoids, gingival epigastric pain,
pain, flatulence, glossitis, tooth
mucositis, cheilitis demineralization
Hepatobiliary Cholestasis, hepatitis
disorders
Skin and Skin Severe skin Palmoplantar
subcutaneous eruption, reactions, vitiligo, erythrodysesthesia Acne, contact
tissue itchiness dry skin, erythema, syndrome, acneiform dermatitis
disorders eczema, dermatitis, hair colour
hyperhidrosis, skin changes, psoriasis, papule,
hypopigmentation, skin growth,
alopecia photosensitivity, abnormal
hair growth, lichenoid
keratosis, colour change
skin, hyperpigmentation,
erythema nodosum, skin
ulcer
Cardiovascular Hot flushes Pericardial effusion, Atrial fibrillation,
disorders palpitations, hypotension, hypertension,
Raynaud syndrome, lymphedema,
flushing vasculitis
Pembrolizumab. Keytruda® 323

Organic system Very Common ≥ 1/1000 Uncommon Rare (≥ 1/10.000 a <


disorders Common to < 1/10 ≥ 1/1,000 to <1/1000 1/1.000)
≥ 1/10
Investigations High AST and ALT, Elevated creatine, high Positive
increased blood gamma autoantibodies,
alkaline phosphatase glutamyltransferase, prolonged QT,
amylase, hyperglycemia, prolonged activated
creatinine, bilirubin, partial thromboplastin
thyrotropin, time, reduced
triiodothyronine, testosterone levels,
triglycerides, free high uric acid,
thyroxine, cholesterol, elevated C-reactive
transaminases, weight, protein, elevated
calcium, eosinophil count
Decreased thyroxine, TSH
Musculoskeletal Arthralgia Myalgia, weakness, Myositis, joint stiffness or Plantar fasciitis,
and connective musculoskeletal swelling, polyarthritis, jaw arthropathy, tendon
tissue pain, limbs pain, pain, bone pain, rib pain, pain, tendinitis,
disorders back pain, arthritis, synovitis, tenosynovitis
muscle spasms and neck pain, muscle
stiffness twitching, rheumatic
polymyalgia
General disorders Fatigue Pyrexia, mucosal Generalized or localised Inflammatory pain,
and inflammation, edema, pain, chest pain, localized edema,
administration site peripheral edema, swelling, impaired reaction in injection
conditions disease gait, chest discomfort, site,
flu-like chills, temperature intolerance,
weight-loss, malaise,
infusion-associated feeling hot, thirsty feeling,
reactions xerosis
Gynaecological Pelvic pain, erectile Dysmenorrhea,
and reproductive dysfunction, menorrhagia hematospermia,
organ disorders genital itching, scrotal
erythema
Metabolism and Anorexia, Diabetes mellitus type 1,
nutrition disorders dehydration hyponatremia,
hypokalemia,
hyperglycemia,
hypophosphatemia,
hypoalbuminemia,
hypertriglyceridemia,
hypocalcemia,
hypercholesterolemia,
hyperuricemia,
hypercalcemia
324 E. Una Cidon

Dose Modifications [5-7]


Toxicity Grade 2 Grade 3 Grade 4 Life- Symptomatic Recurrence of
threatening toxicity as
grade 2-3-4
Pneumonitis Withhold D*
Colitis Withhold Withhold D
Nnephritis Withhold D
Hyperthyroidism Withhold
AST or ALT Withhold D
Total bilirubin Withhold D D
Hypophysitis Withhold**
Infusion reactions D
Other Withhold Withhold
* D: permanently discontinue.
** If diabetes mellitus type 1 with hyperglycemia >3 xULN or ketoacidosis, pembrolizumab should be
withheld and if improvement to grade 2 or less or able to control it with hormonal replacement
therapy, it can be restarted.
Resume pembrolizumab when adverse reaction is recovered to Grade 1 or less.

Note

If liver metastasis at the beginning of the treatment, pembrolizumab should be


permanently discontinued if AST or ALT increases by > 50% compare to baseline and does
not reduce in 1 week.
It should also be permanently discontinued if persistent Grade 2 or 3 adverse side-effects
that do not recover to Grade 0-1 within 12 weeks after last dose or unable to reduce steroids
dose to 10 mg or less/daily of prednisone or equivalent within 12 weeks.
Hypothyroidism can be controlled with levothyroxine without stopping pembrolizumab.

Interactions [5-7]

Avoid systemic steroids or immunosuppressive agents before starting the treatment as


they could affect the efficacy of pembrolizumab. However, they could be used to treat
adverse reactions.
No formal pharmacokinetic studies with pembrolizumab have been performed.

CONCLUSION
Pembrolizumab was the first anti-PD-1 antibody to be approved by the FDA for the
treatment of patients with unresectable or metastatic melanoma with disease progression
following ipilimumab, and if BRAF (V600) mutation positive, a BRAF inhibitor. It is also
approved in metastatic NSCLC across all histologies and tumours which express PD-L1, after
Pembrolizumab. Keytruda® 325

progression on or after platinum-containing chemotherapy, as well as a targeted agent in


epidermal growth factor receptor– or anaplastic lymphoma kinase–positive patients [1-4].
Pembrolizumab is now the second FDA-approved PD-1 inhibitor in lung cancer and the
first across all NSCLC histologies [4].
There are a number of ongoing clinical trials investigating the role and optimal use of
these immunotherapeutic agents either alone or in combination with another
immunotherapeutic drug or chemotherapy in different types of tumours. Results are awaited
to accurately define the future plans of treatment [1-4].

REFERENCES
[1] Dang TO, Ogunniyi A, Barbee MS, Drilon A. Pembrolizumab for the treatment of PD-
L1 positive advanced or metastatic non-small cell lung cancer. Expert Rev. Anticancer.
Ther. 2015 Nov 20.
[2] Scarpace SL. Metastatic squamous cell non-small-cell lung cancer (NSCLC): disrupting
the drug treatment paradigm with immune- therapies. Drugs Context. 2015; 4:212289.
[3] Raedler LA. Keytruda (Pembrolizumab): First PD-1 Inhibitor Approved for Previously
Treated Unresectable or Metastatic Melanoma. Am. Health Drug Benefits. 2015;8(Spec
Feature):96-100.
[4] Roxanne Nelson. FDA Approves Pembrolizumab for Lung Cancer. http://www.med
scape.com/viewarticle/852054.
[5] Keytruda (pembrolizumab) - Medscape Reference. http://reference. medscape.com/
drug/keytruda-pembrolizumab-999962.
[6] Pembrolizumab - Food and Drug Administration. http://www. accessdata.fda.gov/
drugsatfda_docs/label/2014/125514lbl.pdf.
[7] Keytruda, INN-pembrolizumab - Europa. http://ec.europa.eu/health/documents/
community-register/2015/20150717132284/anx_132284_es. pdf.
In: The Easy Book of Cancer Pharmacology ISBN: 978-1-63485-038-4
Editor: Esther Una Cidon © 2016 Nova Science Publishers, Inc.

Chapter 37

PEMETREXED. ALIMTA®

M. Uherek
University Hospital Southampton NHS Foundation Trust, Southampton, UK

ABSTRACT
Pemetrexed disodium is a multitarget antifolate [5], which disrupts folate-dependent
metabolic pathways essential for normal cellular function, mainly DNA synthesis,
necessary for cell replication [6]. Pemetrexed causes cell cycle arrest in G1/S [4].
Pemetrexed is a radiosensitizer [9], however, its concurrent use with radiotherapy has not
been widely adopted outside of clinical trials [10]. Pemetrexed is currently approved for
use in malignant mesothelioma, locally advanced and metastatic non-small lung cancer
(NSCLC) with non-squamous histology. It is used in conjunction with platinum agent, as
well as a single agent in maintenance therapy. Common side-effects such a
myelosuppresion, mucositis and diarrhoea are reduced by administration of folic acid and
vitamin B12. Skin rashes are common, however, the severity and incidence of skin
reactions is reduced by premedication with corticosteroids [4]. The only route of
administration of pemetrexed is intravenous (iv) [2].

Keywords: pemetrexed, non-small cell lung cancer

INTRODUCTION
Pemetrexed was designed and synthethised by American chemist Edward C. Taylor at
Princeton University and approved by the Food and Drug Administration (FDA) for use in
pleural mesothelioma in combination with cisplatin in 2004 [13].
Pemetrexed has a high affinity to the reduced folate carrier that facilitates its entry into
the cell where it is extensively polyglutamated [4, 7]. Glutamation increases intracelullar half-
life and retention of pemetrexed. This antineoplastic agent has multiple enzyme targets
involved in thymidine and purine synthesis [8]. It inhibits thymidylate synthase (TS),


Maja Uherek, e-mail: maja.uherek@googlemail.com.
328 M. Uherek

dihydrofolate reductase (DHFR), glycinamide ribonucleotide formyltransferase (GARFT) [2]


and aminoimidazole carboxamide formyl transferase (AICARFT) [9]. These are the key
enzymes in the process of de novo synthesis of purine nucleotides and thymidine.
Polyglutamated metabolites of pemetrexed are 60-fold more potent inhibitors of TS than
monoglutamated forms. Process of polyglutamation occurs in tumour cells and to a lesser
extent in normal cells [8].

CLINICAL PHARMACOLOGY
Drug Classification

Antifolate antimetabolite.

Pharmacokinetics

Absorption Administered iv only. Peak plasma levels are reached in <30 mins [1]
Distribution Volume of distribution 6.8-9 l/m2
Plasma and interstitial compartments
Protein binding 81%
Metabolism Negligible
Excretion Primarily in urine. 70-90% of the dose eliminated in urine within 24 h
Clearance 91.8 ml/min (total interpatient variability is 19.3%)
Terminal half life 2.2-7.2h, depends on the renal function
*
Adapted from [2, 4].

Mechanisn of Resistance [1]

 Increased expression of TS
 Reduced binding affinity of TS to pemetrexed
 Decreased polyglutamation
 Decreased transport of drugs into cells (decreased expression of reduced folate
carrier and proton-coupled folate transporter)

Indications [1]

1. Malignant pleural mesothelioma in combination with platinum agent.


2. Advanced and metastatic non-small cell lung cancer (NSCLC) with non-squamous
histology in combination with platinum-based chemotherapy and as maintenance
treatment in patients whose disease has not progressed after combination
chemotherapy.
Pemetrexed. Alimta® 329

Dosages

The recommended dose of pemetrexed is 500 mg/m2 body surface area (BSA) on day 1
of each 21-day cycle in combination with platinum agent or as a single agent in maintenance
therapy.

Methods of Preparation/Administration [2, 3]

Pemetrexed disodium 100 mg and 500 mg powder for concentrate for solution for
infusion.
White to either light yellow or green-yellow lyophilised powder.
Reconstitute 100-mg vials with 4.2 ml of 0.9% sodium chloride or 500-mg vials in 20 ml
of 0.9% of sodium chloride resulting in a solution containing 25 mg/ml pemetrexed. Swirl
each vial until powder is completely dissolved, then dilute it further with 100 ml of 0.9%
sodium chloride and administer as iv infusion over 10 minutes [2].
Pemetrexed is physically incompatible with diluents containing calcium, including
Ringer lactate for injection and Ringer‘s injection. In the absence of compatibility studies,
this medicine must not be mixed with others.

Special Information and Cautions

Contraindications [2]
Breast-feeding
Hypersensitivity to pemetrexed or to any of the excipients listed below:

 Mannitol
 Hydrochloric acid
 Sodium hydroxide

Concomitant yellow fever vaccine.

Elderly
As elderly patients are more likely to have decrease renal function, caution should be
applied in dose selection. No dose reductions are necessary for those patients older than 65
other than those recommended for all patients.

Pediatric
Safety and effectiveness have not been established.

Renal Impairment
Decreased renal function will result in greater exposure to the drug. Pemetrexed
combined with cisplatin has not been studied in moderate renal impairment.
Do not administer if CrCL less than 45 mls/min.
330 M. Uherek

Hepatic Impairment
No effect of elevated transaminases or bilirubin on the pharmacokinetic of this drug.

Warnings

Contraception
Women of childbearing age must use effective contraception during treatment with
pemetrexed. Sexually mature males should not father a child during the treatment and up to 6
months thereafter due to genetically damaging effects [3].

Third Space
Drainage of ascites or pleural effusion prior to treatment with pemetrexed should be
considered due to the risk of third space accumulation, however it may not be necessary [2].

Concomitant Use of Non-Steroidal Anti-Inflammatories (NSAIDs)

NSAIDs with Short Half-Lives


If creatinine clearance (CrCL) above or equal to 80 mL/minute is safe and no dose
adjustment is necessary [10], however, high doses should be used with caution [3].
If CrCL is between 45 and 79 mL/minute NSAIDs with short half-lives (ibuprofen,
ketoprofen, ketorolac, indomethacin) should be discontinued 2 days before and 2 days after
administration of pemetrexed.

NSAIDs with Long Half-Lives


Such as naproxen, nabumetone, piroxicam, oxaprozin, should be discontinued 5 days
prior to chemotherapy and restarted no sooner than 2 days after administration of pemetrexed
even in patients with normal renal function [10].

Premedications
Steroids: To reduce the incidence and severity of skin reactions patients should receive
4mg of dexamethasone (or equivalent) orally twice a day for three days beginning 1 day prior
to chemotherapy.
Folic acid and B12: To reduce toxicity patients should receive oral folic acid 350-1000
mcg daily starting 1 week before therapy. Folic acid should be taken daily and for 21 days
after the last dose of pemetrexed. Patients must also receive an intramuscular injection of
vitamin B12 1000 micrograms 1 week prior to the start of pemetrexed and once every three
cycles thereafter. Subsequent vitamin B12 injections may be given on the same day as
chemotherapy.

Interactions

1. NSAIDs [2]
See Warnings section.
Pemetrexed. Alimta® 331

2. Vaccines
Yellow fever vaccine: risk of fatal generalised vaccinale disease [2].
Live attenuated vaccines not recommended [2].

3. Nephrotoxic DRUGS
Such as aminoglycosides, loop diuretics, cyclosporine, platinum agents, could result in
delayed clearance of pemetrexed, therefore renal fuction should be closely monitored.

4. Concurrent Administration of Tubularly Secreted Substances


Such as probenecid and penicillin, could result in delayed clearance of pemetrexed [2].

Toxicities [2, 3]

Organic Very common Common ≥1/100 Uncommon Rare


disorders ≥1/10 and <1/10 ≥1/1000 and ≥1/10,000 and
<1/100 <1/1000
Hair and skin Rash/ Urticaria, Radiation recall
disorders desquamation erythema (weeks or years post
multiforme, administration)
pruritus bullous conditions,
including Stevens-
Johnson syndrome
and toxic epidermal
necrolysis
Vascular Peripheral ischaemia
disorders (leading sometimes to
extremity necrosis),
pulmonary embolism
Cardiac Myocardial infarction,
disorders angina pectoris,
supraventricular
arrhythmias
General Fatigue Dehydration, pain,
disorders oedema
Neurological Sensory Neuropathy - Cerebrovascular
disorders neuropathy motor, dizziness accident, transient
ischaemic attack
Gastrointestinal Nausea, vomiting, Dyspepsia, Colitis (including
disorders anorexia, abdominal pain, bleeding, sometimes
diarrhoea, heartburn, taste fatal, intestinal
constipation disturbance perforation, intestinal
Stomatitis/ necrosis, and
pharyngitis typhlitis),
oesophagitis/
radiation,
oesophagitis
332 M. Uherek

(Continued)

Organic Very common Common ≥1/100 Uncommon Rare


disorders ≥1/10 and <1/10 ≥1/1000 and ≥1/10,000 and
<1/100 <1/1000
Investi- Creatinine ALT, AST and Pancytopenia
gations elevation, GGT elevation
decreased
creatinine
clearance
Blood and Anaemia, Pancytopenia,
lymphatic leucopenia, haemolytic anaemia
disorders thrombocyto-
penia,
neutropenia
Renal Creatinine Renal failure
disorders elevation
Hepatobiliar ALT, AST and Hepatitis
y disorders GGT elevation
Respiratory Chest pain Pulmonary
and thoracic embolism,
disorders interstitial
pneumonitis with
respiratory
insufficiency
(sometimes fatal),
radiation
pneumonitis
Eye and ear Conjunctivitis
disorders
Infections Febrile
and neutropenia and
infestations infection without
neutropenia
Immunologic Allergic
al disorders reaction/
hypersensitivity

Dose Modification

In renal impairement [10, 11]


CrCL higher or equal to 45 mL/min – no dose adjustment necessary.
CrCL lower than 45 mL/minute – use is not recommended.
In hepatic impairement [10]
Transaminase elevation >5.1 ULN – dose reduction to 75%
Obesity [12]
Utilize patient‘s actual body weight (full weight) for dose calculation.
Pemetrexed. Alimta® 333

CONCLUSION
Pemetrexed is widely used in treatment of mesothelioma and NSCLC with non-squamous
histology. Its efficacy has been tested in multiple clinical trials. EMPHACIS was a
multicentre, randomised, single-blinded phase III trial, which randomised 456 patients with
pleural mesothelioma to receive cisplatin/pemetrexed or cisplatin/placebo. Median overall
survival (OS) was significantly longer in the pemetrexed/cisplatin arm (12.1 versus 9.3
months) as it was time to progression (TTP) 5.7 versus 3.9 months. Difference in OS was
most striking in patients who received B12 and folic acid supplements, as these experienced
less toxicity and thus they were able to receive more cycles of chemotherapy [14].
Two non-randomised phase II trials, looked at the efficacy of pemetrexed in combination
with carboplatin. Results showed that carboplatin may be a reasonable alternative in patients
where cisplatin toxicity may be a concern. TTP 6.5 months, OS 12.7 months and objective
response 17% [15, 16].
Role of pemetrexed in the second line setting was evaluated in phase III multicentre trial,
in which 243 patients with mesothelioma were randomly assigned to receive single-agent
pemetrexed as second-line therapy or best supportive care. This study did not show
improvement in OS; however, median progression-free survival was longer in the pemetrexed
arm (3.6 months versus 1.5 months) [17].
A large phase III non-inferiority randomized trial looked at the efficacy of pemetrexed
and cisplatin versus gemcitabine and cisplatin in chemotherapy-naive patients with stage IIIB
and IV NSCLC. Patients were randomly assigned to two arms. Results showed that OS in the
pemetrexed/cisplatin arm was non-inferior to cislatin/gemcitabine. What is more important,
this trial showed that patients with adenocarcinoma had a higher OS if treated with
pemetrexed combination (12.6 versus 10.9 months). Similar trend was observed in patients
with large-cell carcinoma histology, where OS in the pemetrexed/cisplatin arm was 10.4
months versus 6.7 months. Interestingly in patients with squamous cell carcinoma OS was
increased in the gemcitabine/cisplatin arm (10.8 versus 9.4 months). This explains why
pemetrexed is not licensed for use in these patients [18].
These encouraging results led to further studies looking at the use of pemetrexed in
maintenance therapy. In PARAMOUNT study 539 patients whose disease responded to
treatment or remained stable after four cycles of cisplatin/pemetrexed, were randomly
assigned to maintenance with pemetrexed or placebo. Median progression-free survival in the
pemetrexed was 4.1 versus 2.8 months in the placebo group. OS was also significantly higher
in the pemetrexed group 13.0 versus 11.0 months [19]. The largest phase III trial looking at
the maintenance therapy after 4 cycles of platinum-based chemotherapy recruited 745
patients. Patients were treated with cisplatin or carboplatin in combination with paclitaxel,
gemcitabine or docetaxel. 663 patients had objective response and were randomly assigned to
maintenance with pemetrexed or placebo. Maintenance with pemetrexed increased median
progression free survival 4.3 versus 2.6 months and OS 13.4 versus 10.6. As a result of these
studies pemetrexed has been licenced for use as maintenance therapy in patients with non-
squamous NSCLC who responded or have stable disease after platinum-based combination
chemotherapy [20].
334 M. Uherek

REFERENCES
[1] Edward Chu, Vincent T. De Vita. Physicians’ Cancer Chemotherapy Drug Manual
2013. London: Jones and Bartlett.
[2] European Medicines Agency. Alimta - summary of product characteristics. Patient
Information Leaflet. Available online. Accessed 05/07/15.
[3] Eli Lilly UK. ALIMTA® Product Information. Available online.
[4] BC Cancer. Pemetrexed monograph. Available online, accessed 07/07/15.
[5] Avendano, Carmen; Menendez, J. Carlos (April 2008). Medicinal Chemistry of
Anticancer Drugs. Amsterdam: Elsevier. p. 37.
[6] Tannock I, Hill R, Bristow R, Harrington L. The Basic Science of Oncology. 5th edition
McGraw-Hill 2013.
[7] DeVita, Hellman, Rosenberg. Cancer. Principles and Practice of Oncology. Volume 2.
8th edition. Lippincott Williams and Wilkins 2008.
[8] Paz-Ares L, Bezares S, Tabernero J et al. Review of a promising new agent -
pemetrexed disodium. Cancer 2003;97 (supplement 8):2056-2063.
[9] Bischof M, Weber K, Blatter J et al. Interaction of pemetrexed disodium and irradiation
in vitro. Int J Radiat Oncol Biol Phys 2002;52(5):1381-1388.
[10] Pemetrexed – drug information. UpToDate®. Available online. Accessed 04/07/2015.
[11] Daniels S. North London Cancer Network, Dose adjustement for cytotoxics in renal
impairement. January 2009. Accessed 05/07/2015. Available online.
[12] Griggs JJ, Mangu PB, Anderson H et al., ― Appropriate Chemotherapy Dosing for
Obese Adult Patients With Cancer: American Society of Clinical Oncology Clinical
Practice Guideline.‖ J Clin Oncol, 2012, 30(13):1553-61.
[13] Taylor, Edward C. Chemistry International, Vol. 33 No. 5 September-October 2011.
[14] Vogelzang NJ, Rusthoven JJ, Symanowski J et al. Phase III study of pemetrexed in
combination with cisplatin versus cisplatin alone in patients with malignant pleural
mesothelioma. J Clin Oncol 2003; 21:2636.
[15] Ceresoli GL, Zucali PA, Favaretto AG et al. Phase II study of pemetrexed in
combination plus carboplatin in malignant pleural mesothelioma. J Clin Oncol 2006;
24:1443.
[16] Castagneto B, Botta M, Aitini E et al. Phase II study of pemetrexed in combination with
carboplatin in patients with malignant pleural mesothelioma (MPM). Ann Oncol 2008;
19:370.
[17] Jassem J, Ramlau R, Santoro A et al. Phase III trial of pemetrexed plus best supportive
care compared with best supportive care in previously treated patients with advanced
malignant pleural mesothelioma. J Clin Oncol 2008; 26:1698.
[18] Scagliotti GV et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin
plus pemetrexed in chemotherapy-naive patients with advanced-st.
Pemetrexed. Alimta® 335

[19] Paz-Ares LG, de Marinis F, Dediu M et al. PARAMOUNT: Final overall survival
results of the phase III study pf maintenence pemetrexed plus best supportive care
versus placebo immediately after induction therapy with pemetrexed plus cisplatin for
advanced nonsquamous non-small cell lung cancer. J Clin Oncol 2013; 31:2895.
[20] Ciuleanu T, Brodowicz T, Zielinski C et al. Maintenence pemetrexed plus best
supportive care versus placebo with best supportive care for non-small cell lung cancer:
a randomised, double-blind, phase 3 study. Lancet 2009; 374:1432.
In: The Easy Book of Cancer Pharmacology ISBN: 978-1-63485-038-4
Editor: Esther Una Cidon © 2016 Nova Science Publishers, Inc.

Chapter 38

PERTUZUMAB. PERJETA

T. Sampedro Gimeno1,, V. Reguero Cuervo1


and P. Garcia-Teijido2
1
Department of Medical Oncology, Cabueñes Hospital, Gijon, Spain
2
Department of Medical Oncology, ―San Ag
ustín‖ Hospital, Aviles, Spain

ABSTRACT
Human epidermal growth factor receptor (HER) 2, a transmembrane tyrosine-kinase
receptor, is a member of the epidermal growth-factor receptor (EGFR) family. In
approximately 20% of breast tumors HER2 is amplified and/or overexpressed. While
HER2-positive tumors represent an aggressive subtype of breast cancer, the prognosis of
these neoplasms has changed dramatically since the introduction of monoclonal
antibodies like trastuzumab, the first one used in this setting. A number of patients
develop primary and secondary resistance to trastuzumab and several therapeutic
strategies to combat this issue have emerged. A common approach is to initiate dual
HER2 blockade by combining two different drugs against HER2, such as trastuzumab
and pertuzumab. Pertuzumab prevents HER2:HER3 dimer formation and subsequent
HER3-mediated signaling. The theoretically complementary mechanisms of pertuzumab
and trastuzumab imply a greater efficacy when used together, as they would provide a
more complete block of downstream signaling. The use of pertuzumab is approved for
HER2-positive metastatic or locally recurrent breast cancer, in combination with
chemotherapy and trastuzumab, where it prolongs progression free survival, overall
survival and objective response rate. The benefits of its use for locally advanced
resectable breast cancer are also promising, improving complete pathologic responses. In
general, pertuzumab is safe and well tolerated, and it appears to have low cardiac
toxicity. In conclusion, it is a fact that pertuzumab has transformed the approach to
HER2-positive disease and further combination strategies will incorporate it as an
essential drug.

Keywords: pertuzumab, HER-2, breast cancer


teresa.sampedro@sespa.es.
338 T. Sampedro Gimeno, V. Reguero Cuervo and P. Garcia-Teijido

INTRODUCTION
HER2 was discovered in the mid-1980s and it is a member of the HER family of
transmembrane receptor tyrosine kinases, which also include HER1, HER3, and HER4. In
breast tumors, gene amplification and/or overexpression of HER2 occurs in approximately
20% of cases. These tumors represent an aggressive subtype of breast cancer, but the
prognosis has changed dramatically since the introduction of antiHER2 therapies, either for
metastatic disease or locally advanced tumors. The abundance of HER2 at the cell surface
facilitates heterodimerization of HER2 with other HER family members [1, 2]. Pertuzumab
blocks ligand-induced HER2–HER3 heterodimers and when used in combination with
inhibitors of ligand-independent homodimerization of HER2 (trastuzumab) it offers a
promising synergistic therapeutic strategy [3].
In this chapter, we focus on Pertuzumab and examine its mechanism of action and
rationale for development, clinical efficacy in various settings, pharmacokinetics, dose and
regimen, safety and tolerability, and current role in the management of breast cancer.

CLINICAL PHARMACOLOGY
Drug Classification

Humanized IgG1 monoclonal antibody produced in mammalian cells by recombinant


technology.

Mechanism of Action

Pertuzumab (rhuMAb 2C4) is a fully recombinant humanized monoclonal antibody that


is based on the human immunoglobulin (Ig) G1(κ) framework sequences. It consists of two
449 residue heavy chains and two 214 residue light chains. It specifically targets the
extracellular dimerization domain (subdomain II) of the HER2 protein, and thereby, blocks
ligand-dependent heterodimerisation of HER2 with other HER family members, including
EGFR, HER3 and HER4. As a result, it inhibits ligand-initiated intracellular signaling
through two major signal pathways, mitogen-activated protein kinase (MAPK) and
phosphoinositide 3-kinase (PI3K). Inhibition of these signaling pathways can result in cell
growth arrest and apoptosis, respectively. In addition, pertuzumab mediates antibody-
dependent cell-mediated cytotoxicity with the same potency as trastuzumab. In HER2-
positive xenograft models, pertuzumab demonstrated synergistic antitumor activity in
combination with trastuzumab or trastuzumab DM-1 (T-DM1) [4].
Pertuzumab. Perjeta 339

PHARMACOKINETICS [5, 6]
Absorption It is administered as an intravenous (iv) infusion. No studies have been
performed with other routes of administration.
Distribution Biphasic distribution pattern, supporting a two-compartment PK model. Across
all clinical studies, the volumes of distribution of the central (Vc) and the
peripheral (Vp) compartment in the typical patient, were 3.11 litres and 2.46
litres, respectively. The distribution phase is less than 24 hours.
Metabolism There is limited data regarding the exact site of pertuzumab metabolism. This is
likely in part because of the historical difficulty in measuring the process of
antibody metabolism. The metabolism has not been directly studied, but it is
known that antibodies are cleared principally by catabolism. The data available
includes evidence that IgG metabolism occurs prominently in the liver, and to a
lesser extent in the kidneys and gastrointestinal tract. Additionally, murine radio-
iodination models have demonstrated antibody clearance occurring
predominantly in the gut (72.8%), followed by the liver (20.5%), and spleen
(3.6%).
Excretion The median clearance (CL) of pertuzumab is 0.235 litres/day and the median
half-life was 18 days.

Mechanism of Resistance

In patients with HER2+ metastatic breast cancer, resistance to anti-HER2 therapies either
as single-agent or in combination with chemotherapy, commonly occurs within months of
starting therapy. Only a fraction of patients with HER2+ metastatic breast cancer respond to
single agent therapies, suggesting de novo mechanisms of resistance in advanced cancers.
These mechanisms include signaling from other HER receptors, compensatory signaling from
receptor tyrosine kinases outside of the HER family, aberrant phosphatidylinositol 3-kinase
(PI3K) signaling as a result of mutations in this pathway, the presence of truncated forms of
HER2 and derepression/activation of compensatory survival pathways and defects in pro-
apoptosis molecules such as BIM, among few others [7, 8].

Indications

Based on the results of the CLEOPATRA clinical trial, it is indicated for the use in
combination with trastuzumab and docetaxel in adult patients with HER2-positive metastatic
or locally recurrent unresectable breast cancer, who have not received previous anti-HER2
therapy or chemotherapy for their metastatic disease. When added to trastuzumab and
docetaxel, pertuzumab prolongs progression free survival from 12.4 to 18.5 months (HR 0,62;
p < 0,0001) [9], and also overall survival and objective response rate as secondary endpoints
[10].
The benefits of pertuzumab in combination with neoadjuvant chemotherapy and
trastuzumab for locally advanced breast cancer are also promising and in fact it is approved
by the Food and Drug Administration (FDA) for this indication, but not in the European
Medicines Agency (EMA) yet. In two phase-II randomized trials (NEOSPHERE AND
340 T. Sampedro Gimeno, V. Reguero Cuervo and P. Garcia-Teijido

TRYPHAENA) the combination arm with trastuzumab plus pertuzumab and chemotherapy
(anthracycline and non-anthracycline-containing regimens) obtains higher pathologic
complete responses, which is known as a very important prognostic factor [11, 12].

Dosages

Phase I and II trials where conducted, exploring fixed, weight-based, or body surface area
(BSA) based dosing. Dosing by weight and also by BSA resulted in serum trough
concentrations lower than that of fixed dosing administration. No differences in the clearance
of pertuzumab were seen at all dose levels. Therefore, the recommended initial loading dose
is 840 mg administered as a 60 minute iv infusion, followed every 3 weeks thereafter by a
maintenance dose of 420 mg administered over a period of 30 to 60 minutes.
If the time between two sequential infusions is less than 6 weeks, the 420 mg dose of
pertuzumab can be administered but if the time between two sequential infusions is 6 weeks
or more, the initial dose of 840 mg should be re-administered in the same conditions as the
loading dose followed by a maintenance dose of 420 mg every 3 weeks [5, 6].

METHODS OF PREPARATION/ADMINISTRATION
Care has to be taken to ensure the sterility of the prepared solution for infusion and must
be prepared by a healthcare professional. It is for single use only and the vial should not be
shaken. 14 ml of pertuzumab concentrate has to be withdrawn from the vial and diluted into a
250 ml polyolefin infusion bag of sodium chloride 9 mg/ml (0.9%) solution for infusion.
After dilution, one ml of solution must contain approximately 3.36 mg of pertuzumab (840
mg/250 ml) for the initial dose (two vials required) and 1.68 mg (420 mg/250 ml) for the
maintenance dose (one vial required). In order to avoid foaming the bag must be inverted to
mix the solution [6].
Pertuzumab is administered iv by infusion and not as an iv push or bolus. For the loading
dose, 60 minutes is the recommended infusion period. If the first infusion is well tolerated,
subsequent infusions can be administered over a period of 30 to 60 minutes. It has been
associated with hypersensitivity and infusion reactions. Following the administration of
pertuzumab it is recommended close observation of the patient for 60 minutes after the first
infusion and during 30-60 minutes after subsequent infusions. If an infusion reaction occurs,
it should be slowed down or interrupted and appropriate medical therapies have to be
administered. Patients must be evaluated and carefully monitored until complete resolution of
signs and symptoms [6].
Pertuzumab is generally administered concomitantly with docetaxel and trastuzumab but
in a sequential way. Trastuzumab and pertuzumab can be given in any order. When the
patient is receiving docetaxel, this should be administered after the monoclonal antibodies.
Pertuzumab. Perjeta 341

SPECIAL INFORMATION AND CAUTIONS


Contraindications [6]

Hypersensitivity to pertuzumab or to the excipients listed below:

 Glacial acetic acid


 L-histidine
 Saccharose
 Polysorbate 20
 Water for injections

Elderly Patients

Based on the population pharmacokinetic analysis, no significant difference was


observed in the pharmacokinetics of pertuzumab between patients <65 years and patients ≥65
years. Although there are limited data about safety and efficacy in patients ≥65, no significant
differences have been observed in patients aged 65 to 75 compared to <65. Therefore, dosage
does not need to be adjusted in ≥65. Minimal data are available in patients age >75 [6].

Pediatric Patients

Safety and efficacy not established [6].

Renal Impairment

No dedicated renal impairment trial has been conducted. Based on the results of the
population pharmacokinetic analysis, pertuzumab exposure in patients with mild (creatinine
clearance [CLcr] 60 to 90 ml/min) and moderate renal impairment (CLcr 30 to 60 ml/min)
was similar to that in patients with normal renal function (CLcr greater than 90 ml/min) [5, 6].
It is not necessary to adjust dosage in patients with mild to moderate renal impairment.
Unable to make a dosage recommendation for patients with severe renal impairment (CLcr
less than 30 mL/min) as there are limited pharmacokinetic data available.

Hepatic Impairment

No clinical studies have been conducted to evaluate the effect of hepatic impairment on
the pharmacokinetics of pertuzumab. A specific dosage recommendation cannot be made [6].
342 T. Sampedro Gimeno, V. Reguero Cuervo and P. Garcia-Teijido

Immunisations

Live vaccines should not be applied while taking the treatment or for at least 6 months
afterwards. Other vaccines can be administered, though may not give as much protection as
usual. In any case, it is safe to be in contact with other people who have had live vaccines as
injections. There can be problems with oral vaccines. Any contacts with someone who has
had oral polio, cholera or typhoid vaccination recently, should be avoided.

WARNINGS
Left Ventricular Dysfunction

Pertuzumab can result in subclinical and clinical cardiac failure manifesting as congestive
heart failure (CHF) and decreased left ventricular ejection fraction (LVEF).
Pertuzumab has not been studied in patients with LVEF <50%, or with CHF, reduction of
LVEF to <50% while prior treatment with trastuzumab or uncontrolled hypertension, recent
myocardial infarction, severe cardiac arrhythmia that needs a treatment or previous exposure
to anthracyclines with cumulative dose of >360 mg/m2 for doxorubicin or its equivalent.
Evaluate LVEF prior to and during treatment (every two to three months for neoadjuvant
and metastatic treatments respectively). See Dose Modifications section.

Embryo-Fetal Toxicity

Exposure to pertuzumab can result in embryofetal death and birth defects. Studies in
animals have resulted in oligohydramnios, delayed renal development, and death. Advise
patients of these risks and the need for effective contraception.

Pregnancy

If pertuzumab has been administered during pregnancy or if patient becomes pregnant


while receiving pertuzumab or within 7 months following last dose in combination with
trastuzumab, immediately report exposure to Genentech Adverse Event Line and monitor for
oligohydramnios.

Lactation

Unknown whether distributed in breast milk. Because of potential for serious adverse
reactions in nursing infants, either the drug should be discontinued or breast feeding should
stop.
Pertuzumab. Perjeta 343

Infusion Related Adverse Effects

Severe hypersensitivity, including anaphylaxis observed. Monitor during and after


infusion.

TOXICITIES
Table 1 summarizes the adverse drug reactions from the pivotal clinical trial
CLEOPATRA [6, 9], in which pertuzumab was given in combination with docetaxel and
trastuzumab. All events in the table were also reported in at least 1% of patients participating
in Pertuzumab monotherapy trials [13-15] although not necessarily considered causally
related to this drug. As Pertuzumab is used in combination with other drugs, it is difficult to
ascertain the causal relationship of an adverse event to a particular medicinal product.

Table 1. Summary of adverse drug reactions (ADRs) from the pivotal clinical trial
CLEOPATRA. Very common events (reported in ≥10% of pertuzumab monotherapy-
treated patients) are marked with bold letters

System organ class Very common (≥1/10) Common Uncommon Rare


(≥1/100 (≥1/1000 (≥1/10,000
to <1/10) to <1/100) and <1/1000)
Infections and Upper respiratory tract Paronychia
infestations infection
Nasopharyngitis
Blood and lymphatic Febrile neutropenia
system Neutropenia
disorders Leucopenia
Anaemia
Thrombocytopenia
Immune system Hypersensitivity/
disorders anaphylactic reaction
Infusion related
reaction/cytokine
release syndrome
Metabolism and Decreased appetite
nutrition disorders
Psychiatric disorders Insomnia
Nervous system Neuropathy peripheral
disorders Peripheral sensory
neuropathy
Headache
Dizziness
Dysgeusia
Eye disorders Lacrimation increased
Cardiac disorders Left ventricular
dysfunction
(including
congestive heart
failure)
344 T. Sampedro Gimeno, V. Reguero Cuervo and P. Garcia-Teijido

Table (Continued)

System organ Very common (≥1/10) Common Uncommon Rare


class (≥1/100 (≥1/1000 (≥1/10,000
to <1/10) to <1/100) and <1/1000)
Respiratory, Dyspnoea Pleural effusion Interstitial lung
thoracic and Cough disease
mediastinal
disorders
Gastrointestinal Diarrhoea
disorders Vomiting
Stomatitis
Nausea
Constipation
Dyspepsia
Skin and Alopecia
subcutaneous Rash
tissue disorders Nail disorder
Pruritus
Dry skin
Musculoskeletal Myalgia
and connective Arthralgia
tissue disorders Muscle spams
General disorders Mucositis/mucosal Chills
and administration inflammation
site conditions Pain
Oedema
Pyrexia
Fatigue
Asthenia

Cardiac toxicity is associated with anti-HER2 therapies mediated by a toxic effect on


cardiac myocytes; [7] However, pertuzumab appears to have lower cardiac toxicity than
trastuzumab. In the CLEOPATRA study, left ventricular dysfunction was documented in
4.4% of patients in the pertuzumab-treated group versus 8.3% of patients in the placebo
group. Grade 3 left ventricular systolic dysfunction (LVSD) occurred in 1.2% of patients in
the pertuzumab treated group versus 2.8% of patients in the placebo group [9].
Clinical trial TRYPHAENA‘s primary end point was to evaluate the cardiac safety of the
pertuzumab and trastuzumab combination, either with anthracycline-containing
chemotherapy, concurrently or sequentially or with non-anthracycline chemotherapy. Low
incidence of symptomatic or asymptomatic cardiac toxicity was observed across the three
arms.
Furthermore, LVSD at any grade was almost the same when anthracyclines were
administered concurrently or sequentially with trastuzumab and pertuzumab (5.6% and 4%),
respectively. LVEF decrease (defined as ≥10% and ≤50%) was slightly higher in the
anthracycline arms, but all patients recovered during the adjuvant treatment [12].
Pertuzumab. Perjeta 345

DOSE MODIFICATIONS
Dose reductions are not recommended. It should be discontinued if trastuzumab treatment
is discontinued. However, if docetaxel is discontinued, treatment with pertuzumab and
trastuzumab may continue until disease progression or unmanageable toxicity.

1. Left ventricular dysfunction

Administration of pertuzumab and trastuzumab should be interrupted for at least 3 weeks


if any of the following:

 Signs and symptoms suggestive of CHF.


 A drop in LVEF to less than 40%
 A LVEF of 40%-45% associated with a fall of ≥10% points below pre-treatment
values.

Pertuzumab and trastuzumab can be reintroduced if the LVEF has recovered to >45% or
40-45% associated with <10% points below pretreatment value. If within approximately 3
weeks, the LVEF has not improved, or has declined further, discontinuation of both must be
considered [6].

2. Hypersensitivity reactions

The infusion rate of pertuzumab may be slowed or interrupted if the patient develops an
infusion-related reaction.
If a severe hypersensitivity reaction/anaphylaxis occurs, discontinue the infusion
immediately and administer appropriate medical therapies.
In case of NCI-CTCAE Grade 4 hypersensitivity reactions (anaphylaxis), bronchospasm
or acute respiratory distress syndrome (ARDS) pertuzumab must be permanently
discontinued [6].

INTERACTIONS
No pharmacokinetic interactions have been observed between pertuzumab and
trastuzumab or docetaxel.
Several studies have evaluated the effects of pertuzumab on the pharmacokinetic of co-
administered cytotoxic agents, including docetaxel, gemcitabine, erlotinib or capecitabine,
and there is no evidence of any interaction between any of these agents.
The administration of pertuzumab and trastuzumab in the same infusion bag will be
assessed for efficacy and safety in the VELVET clinical trial utilizing the dual anti-HER2
therapy in combination with vinorelbine [5, 6].
346 T. Sampedro Gimeno, V. Reguero Cuervo and P. Garcia-Teijido

CONCLUSION
The field of breast cancer, particularly HER2-positive breast cancer, is now expanding
with the addition of multiple active targeted therapies. In the footsteps of trastuzumab,
pertuzumab is the next great breakthrough in the treatment of these tumors. Pertuzumab has
already transformed and will continue to transform the approach to HER2-positive disease,
showing improved benefits when given in combination with trastuzumab. Dual anti-HER2
therapy maximally shuts down the HER2 oncogenic pathway and has revolutionized the
medical approach to these patients. Further combination strategies incorporating pertuzumab
and studies elucidating the most effective sequence of anti-HER2 therapy are in progress.
In the future, we anticipate the routine use of genomics to identify biomarkers and
accordingly select patients who will optimally benefit from particular anti-HER2 agents or
therapy combinations. In addition, we expect increased utilization of neoadjuvant trials for
drug development, biomarker discovery, and validation.

REFERENCES
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[2] Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast
cancer: correlation of relapse and survival with amplification of the HER-2/neu
oncogene. Science. 1987;235 (4785):177–182.
[3] Franklin MC, Carey KD, Vajdos FF, Leahy DJ, de Vos AM, Sliwkowski MX. Insights
into ErbB signaling from the structure of the ErbB2-pertuzumab complex. Cancer Cell.
2004;5(4):317–328.
[4] Hubalek M, Brantner C, Marth C. Role of pertuzumab in the treatment of HER2-
positive breast cancer. Breast Cancer (Dove Med Press) 2012;4:65-73.
[5] Maly JJ, Macrae ER. Pertuzumab in Combination with Trastuzumab and Chemotherapy
in the Treatment of HER2-Positive Metastatic Breast Cancer: Safety, Efficacy, and
Progression Free Survival. Breast Cancer (Auckl) 2014;8:81-88.
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[7] Capelan M, Pugliano L, De Azambuja E, Bozovic I, Saini KS, Sotiriou C, Loi S,
Piccart-Gebhart MJ. Pertuzumab: new hope for patients with HER2-positive breast
cáncer. Ann Oncol 2013;24:273-282.
[8] Reynolds K, Sarangi S, Bardia A, Dizon DS. Precision medicine and personalized
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[9] Baselga J, Cortés J, Kim SB, Im SA, Hegg R, Im YH, Roman L, Pedrini JL,
Pienkowski T, Knott A, Clark E, Benyunes MC, Ross G, Swain SM; CLEOPATRA
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Study Group. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer.
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metastatic breast cancer. N Engl J Med 2015;372:724-734.
[11] Gianni L, Pienkowski T, Im YH et al. Efficacy and safety of neoadjuvant pertuzumab
and trastuzumab in women with locally advanced, inflammatory, or early HER2-
positive breast cancer (NeoSphere): a randomised multicentre, openlabel, phase 2 trial.
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[12] Schenewweiss A, Chia S, Hickish T et al. Neoadjuvant pertuzumab and concurrent with
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[13] Agus DB1, Gordon MS, Taylor C, Natale RB, Karlan B, Mendelson DS, Press MF,
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[15] Gianni L, Lladó A, Bianchi G, Cortes J, Kellokumpu-Lehtinen PL, Cameron DA, Miles
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In: The Easy Book of Cancer Pharmacology ISBN: 978-1-63485-038-4
Editor: Esther Una Cidon © 2016 Nova Science Publishers, Inc.

Chapter 39

REGORAFENIB. STIVARGA®

M. López-Gómez, B. García de Santiago, C. Martín,


M. Caridad Miguel1 and E. Casado
Medical Oncology Department,
University Hospital ―I
nfanta Sofia,‖ Madrid, Spain

ABSTRACT
Regorafenib is an oral multikinase inhibitor that selectively targets three pathological
processes implicated in cancer formation: oncogenesis, angiogenesis and the tumor
microenvironment. To achieve these goals, regorafenib inhibits key signaling proteins,
such as BRAF, RAF1, KIT and RET (involved in oncogenesis), platelet-derived growth
factor receptor (PDGFR)-β and fibroblast growth factor receptor (FGFR) (stromal kinases
that support the tumor microenvironment) and suppresses tyrosine kinases involved in
angiogenesis such as VEGF receptor (VEGFR-1, -2, and -3) [1].
Regorafenib is approved for the treatment of patients with metastatic colorectal
cancer (mCRC) previously treated with fluoropyrimidine, oxaliplatin and irinotecan, an
anti-VEGF agent and an anti-EGFR therapy in case of wild-type RAS tumors.
Its approval is based upon the results of the CORRECT trial, which compared best
supportive care (BSC) plus regorafenib (160 mg orally once daily for three of every four
weeks) or placebo in 760 patients with chemotherapy refractory disease (patients had
progressed after all available approved therapies). It demonstrated a modest but
significant survival benefit for regorafenib (median 6.4 versus 5 months, Hazard Ratio
0.77). Based on these results, it has been incorporated in the latest version of mCRC
guidelines [2].
In this setting only a little objective antitumor response was observed [3] whereas
regorafenib has demonstrated a significant increase in progression free survival (PFS) in
patients with metastatic gastrointestinal tumors (GISTs) which have progressed on
previous treatment with imatinib and sunitinib: 4.8 months versus 0.9 months (HR 0.27,
95% CI 0.19-0.39) [4].
Although it has got several side-effects, generally toxicities are manageable.


Email: miriam.lopez@movistar.es.
350 M. López-Gómez, B. García de Santiago, C. Martín et al.

Keywords: regorafenib, colorectal cancer, GIST

INTRODUCTION
Regorafenib, an oral multikinase inhibitor [1], was granted orphan drug status by the
Food and Drug Administration (FDA) in 2011 for the treatment of patients with GISTs. In
September 2012 FDA approved this drug for the treatment of mCRC refractory to all
available treatments [2, 3] and finally in February 2013 FDA approved it to treat locally
advanced, unresectable or metastatic GIST previously treated with imatinib and sunitinib.
This approval was based on data from the pivotal phase III study GRID (GIST-Regorafenib in
progressive disease) [4]. This showed that regorafenib plus BSC significantly improved PFS
compared to placebo plus BSC (4.8 versus 0.9 months).
Liver function tests (ALT, AST and bilirubin) must be obtained before initiation of
regorafenib and monitored at least every two weeks during the first 2 months of treatment.

CLINICAL PHARMACOLOGY
Drug Classification

Regorafenib is an oral protein tyrosine kinase inhibitor.

Mechanism of Action

Regorafenib is a small molecule inhibitor of multiple membrane-bound and intracellular


kinases involved in normal cellular functions and in pathologic processes such as
oncogenesis, tumor angiogenesis and maintenance of the tumor microenvironment [1].
Regorafenib inhibits the activity of RET, VEGFR1, VEGFR2, VEGFR3, KIT, PDGFR-
alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, TrkA, Eph2A, RAF-1, BRAF,
BRAFV600E, SAPK2, PTK5, and Abl [1].

Pharmacokinetics
Absorption Mean peak plasma level at 3-4 hours after a single oral dose of 160 mg.
Distribution Regorafenib undergoes enterohepatic circulation with multiple plasma concentration peaks across the 24-
hour dosing interval. Highly bound (99.5%) to human plasma proteins.
The main circulating metabolites are M-2 (N-oxide) and M-5 (N-oxide and N-desmethyl). Both of them
are highly protein bound (99.8% and 99.95%, respectively)…. Te lo he cambiado de sitio (estaba en
metabolismo)
Metabolism Regorafenib is metabolized by CYP3A4 (oxidative metabolism in the liver) and glucuronidation by
UGT1A9. The main circulating metabolites, M-2 and M-5, are pharmacologically active and have
similar concentrations as regorafenib at steady state, with similar metabolism.
Elimination Mean elimination half-life for regorafenib and the M-2 metabolite in plasma are 28 hours (14 to 58
hours) and 25 hours (14 to 32 hours), respectively. M-5 has a longer mean (range) elimination half-life of
51 hours (32 to 70 hours). Approximately 71% of a radiolabeled dose was excreted in faeces and 19% of
the dose was excreted in urine.
Regorafenib. Stivarga® 351

Mechanism of Resistance

Recently it has been observed a close association of increase expression of interleukin 1


receptor (IL1R2) and regorafenib resistance in cell lines of CRC. It has been demonstrated
that silencing of IL1R2 overcame resistance to regorafenib, whereas overexpression of IL1R2
decreased the sensitivity to regorafenib in vitro and in vivo systems. Apparently regorafenib
significantly increased the expression of extracellular-signal-regulated kinase (Erk) which is a
survival factor in IL1R2 cells. Thus, pretreatment of IL1R2-overexpressing CRC cells with
Erk inhibitor reversed their resistance [5].
Further studies are necessary to draw final conclusions.

Indications

Regorafenib is indicated for the treatment of:

1. mCRC previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based


chemotherapy, an anti-VEGF therapy, and, if wild type RAS, an anti-EGFR therapy
[2].
2. Locally advanced, unresectable or metastatic GISTs previously treated with imatinib
mesylate and sunitinib malate [4].

Dosages [6]

The recommended dose is 160 mg (four 40 mg tablets) taken orally once daily for the
first 21 days of each 28-day cycle. Treatment must be continued until disease progression or
unacceptable toxicity.

Methods of Administration [6]

Regorafenib is a 40 mg, light pink, oval shaped, film-coated tablet, debossed with
‗BAYER‘ on one side and ‗40‘ on the other side.
Tablets should be taken at the same time each day. It is recommended to swallow tablet
whole with a low-fat breakfast that contains less than 30% fat (i.e., 2 slices of white toast with
1 tablespoon of low-fat margarine and 1 tablespoon of jelly, and a glass of skim milk).
Patients never must take two doses of regorafenib on the same day to make up for a missed
dose from the previous day.
352 M. López-Gómez, B. García de Santiago, C. Martín et al.

SPECIAL INFORMATION AND CAUTIONS [6]


Contraindications

None.

Elderly Patients

No overall differences in safety or efficacy have been observed between elderly and
younger patients. 39% of the total number of patients included in regorafenib studies were
over 65 and 8% over 75.

Pediatric Patients

The safety and efficacy of regorafenib in patients less than18 years of age have not been
established.

Renal Impairment

No dose adjustment is recommended for patients with mild renal impairment as no


clinically relevant differences in the mean exposure of regorafenib and the active metabolites
(M-2 and M-5) were seen in patients with mild renal impairment (CLcr 60-89
mL/min/1.73m2) compared to patients with normal renal function following regorafenib 160
mg daily for 21 days.
There are limited pharmacokinetic data from patients with moderate renal impairment
(CLcr 30-59 mL/min/1.73m2).
Regorafenib has not been studied in patients with severe renal impairment or end-stage
renal disease.

Hepatic Impairment

No dose adjustment is recommended in patients with mild or moderate hepatic


impairment as no clinically important differences in the mean exposure of regorafenib or the
active metabolites (M-2 and M-5) have been observed in patients with hepatocellular
carcinoma and mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment
compared to patients with normal hepatic function. It is mandatory to closely monitor these
patients for adverse reactions.
Regorafenib is not recommended in patients with severe hepatic impairment (Child-Pugh
Class C) as it has not been studied in this population.
Regorafenib. Stivarga® 353

WARNINGS [6]
Hepatotoxicity

Liver function tests (ALT, AST and bilirubin) must be obtained before initiation of
regorafenib and monitored at least every two weeks during the first 2 months of treatment.
Thereafter, it must be monitored at least monthly or more frequently according to physician.
Liver function tests must be monitored weekly in patients experiencing elevated liver function
tests until improvement to less than 3 times the ULN or baseline. Regorafenib must be
temporarily held and then reduced or permanently discontinued depending on the severity and
persistence of hepatotoxicity (hepatotoxicity is manifested by elevated liver function tests or
hepatocellular necrosis) (For management of hepatotoxicity see table below).

Grade ALT and/or AST Ocurrence Recommended measures


elevations
≤Grade 2 ≤5 x ULN Any ocurrence Continue treatment
Monitor liver function weekly until
transaminases return to <3 x ULN or baseline
≥Grade 2 with >3 x ULN Any ocurrence Discontinue treatment permanently.
concurrent BR Monitor liver function weekly until resolution
> 2 x ULN or return to baseline
Grade 3 >5 × to ≤20 × First ocurrence Interrupt treatment
ULN Monitor transaminases weekly until levels
return to <3 x ULN or baseline
Patients may restart treatment if the potential
risk outweights the risk of liver toxicity
To restart treatment reduce dose by 1 tablet
(40 mgr) and monitor liver function weekly
for at least 4 weeks.
Recurrence Discontinue treatment permanently
Grade 4 > 20 xULN Any ocurrence Discontinue treatment permanently
Notes: a Grading by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-
CTC) (version 4.03.2010); b exception: patients with Gilbert‘s syndrome who develop elevated
transaminases should be managed as per the outlined recommendations for the respective observed
elevation of ALT and/or AST. Abbreviations: ALT, alanine aminotransferase; AST, aspartate
aminotransferase; ULN, upper limit of normal.

Hemorrhage

Regorafenib must be permanently discontinued in patients with severe or life-threatening


hemorrhage. It is also advisable to monitor INR levels more frequently in patients receiving
warfarin.

Hand-Foot Skin Reaction (HFSR)

It is also known as palmo-plantar erythrodysesthesia. It may develop soon after a patient


starts therapy, usually within the first 2–4 weeks of initiating treatment. Proactive
354 M. López-Gómez, B. García de Santiago, C. Martín et al.

management should be implemented before skin lesions develop, to reduce the severity of the
symptoms. Patients should be advised to remove any calluses on their hands and feet, to
protect pressure points with cotton gloves/socks, and the prophylactic topical use of urea-
based cream. To minimize the risk of HFSR hot water should be avoided when washing,
showering and bathing.

Hypertension

Blood pressure should be measured and adequately controlled before starting treatment.
After starting treatment, blood pressure should be monitored weekly for the first 6 weeks of
treatment and patients should be advised to regularly perform home blood pressure
monitoring.
Patients should also be advised to record their blood-pressure readings in a diary and
notify the health care team of any elevations.
If high blood pressure develops during regorafenib treatment, there are several classes of
oral antihypertensive agents that can be prescribed: thiazide diuretics, beta blockers,
dihydropyridine and non-dihydropyridine calcium channel antagonists, angiotensin-
converting enzyme inhibitors, and angiotensin-receptor antagonists. The JNC 7 guidelines
recommend using two agents when blood pressure is 20/10 mmHg above target blood-
pressure range; generally one of these medications will be a thiazide diuretic.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS)

A syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI


must be suspected in any patient presenting with seizures, headache, visual disturbances,
confusion or altered mental function. In these cases regorafenib must be discontinued.

Gastrointestinal Perforation or Fistula

Regorafenib must be permanently discontinued in patients who develop gastrointestinal


perforation or fistula.

Wound Healing Complications

Since vascular endothelial growth factor receptor (VEGFR) inhibitors such as regorafenib
can impair wound healing, treatment with regorafenib should be stopped at least 2 weeks
prior to scheduled surgery. Regorafenib should be discontinued in patients with wound
dehiscence.
Regorafenib. Stivarga® 355

Embryo-Fetal Toxicity

Regorafenib can cause fetal harm when administered to a pregnant woman. Regorafenib
was embryolethal and teratogenic in rats and rabbits.
It is important not to become pregnant or father a child while having treatment and for a
few months afterwards.

Breastfeeding

Do not breastfeed during this treatment because the drug may come through in the breast
milk.

IMMUNISATIONS
Live vaccines should not be applied while taking the treatment or for at least 6 months
afterwards. Other vaccines can be administered, though may not give as much protection as
usual. In any case, it is safe to be in contact with other people who have had live vaccines as
injections. There can be problems with oral vaccines. Any contacts with someone who has
had oral polio, cholera or typhoid vaccination recently, should be avoided.

TOXICITIES [6]
System organ Very common Common Uncommon Rare
class (≥1/10) (≥1/100 to <1/10) (≥1/1000 to (≥1/10,000 and <1/1000)
<1/100)
Vascular Hypertension, Hypertensive crisis
disorders hemorrhage
Skin and Palmar-plantar Stevens-Johnson
subcutaneous erythrodysesthesia syndrome, toxic
tissue disorders (HFSR), rash, epidermal necrolysis,
alopecia erythema multiforme,
skin cancer
(keratoacanthoma,
squamous cell carcinoma)
Infections and Infections
infestation
disorders
Endocrine Hypothyroidism
disorders
Metabolism and Appetite
nutrition decreased, weight
disorders loss
Nervous system Headache Tremor Reversible posterior
disorders encephalopathy syndrome
(RPLS)
356 M. López-Gómez, B. García de Santiago, C. Martín et al.

(Continued)

System organ Very common Common Uncommon Rare


class (≥1/10) (≥1/100 to <1/10) (≥1/1000 to (≥1/10,000 and <1/1000)
<1/100)
Cardiac disorders Myocardial Bradycardia
ischemia and
infarction
Gastrointestinal Diarrhea, Gastroesophageal Gastrointestinal fistula
disorders mucositis, nausea, reflux,
vomiting taste disturbance,
xerostomia
Hepatobiliary AST increased, Liver injury (severe), liver
disorders ALT increased, failure
hyperbilirubinemia
Respiratory, Dysphonia Dyspnea
thoracic and
mediastinal
disorders
Renal and Proteinuria
urinary disorders
General disorders Fatigue, pain, Stiffness
and fever
administration
site conditions
investigations