470 Current Drug Metabolism, 2009, 10, 470-481

Tyrosine Kinase Inhibitors – A Review on Pharmacology, Metabolism and Side

Effects

Jörg Thomas Hartmann1,*, Michael Haap2, Hans-Georg Kopp1 and Hans-Peter Lipp3

1
Department of Oncology/Hematology/Immunology/Rheumatology/Pneumology, South West German Cancer Center, Eberhard Karls
University Tübingen, 72076 Tübingen, Germany; 2Department. of Endocrinology, Metabolism, Nephrology, Clinical Chemistry and
Vascular Medicine, 72076 Tübingen, Germany; 3Department of Clinical Pharmacy, 72076 Tübingen, Germany

Abstract: Tyrosine kinase inhibitors (TKI) are effective in the targeted treatment of various malignancies. Imatinib was the first to be in-
troduced into clinical oncology, and it was followed by drugs such as gefitinib, erlotinib, sorafenib, sunitinib, and dasatinib. Although
they share the same mechanism of action, namely competitive ATP inhibition at the catalytic binding site of tyrosine kinase, they differ
from each other in the spectrum of targeted kinases, their pharmacokinetics as well as substance-specific adverse effects. With variations
from drug to drug, tyrosine kinase inhibitors cause skin toxicity, including folliculitis, in more than 50% of patients. Among the tyrosine
kinase inhibitors that are commercially available as yet, the agents that target EGFR, erlotinib and gefitinib, display the broadest spec-
trum of adverse effects on skin and hair, including folliculitis, paronychia, facial hair growth, facial erythema, and varying forms of fron-
tal alopecia. In contrast, folliculitis is not common during administration of sorafenib and sunitinib, which target VEGFR, PDGFR,
FLT3, and others, whereas both agents have been associated with subungual splinter hemorrhages. Periorbital edema is a common ad-
verse effect of imatinib.
Besides the haematological side effects of most of TKIs like anemia, thrombopenia and neutropenia, the most common extra-
heamatologic adverse effects are edema, nausea, hypothyroidism, vomiting and diarrhea. Regarding possible long term effects, recently
cardiac toxicity with congestive heart failure is under debate in patients receiving imatinib and sunitinib therapy; however, this observa-
tion was probably relate to patients selection, although, TKIs overall appear to be a very well tolerated drug class.

IMATINIB MESYLATE Toxicity Profile

Imatinib (STI571), an inhibitor of bcr-abl tyrosine kinase, has
become the first-line agent in the treatment of Ph+ chronic phase
CML (chronic myeloid leukaemia) and of locally advanced and
metastatic gastrointestinal stromal tumors (GIST) that express
CD117 antigens. The recommended dosage is 400 mg/day in pa-
tients with chronic myeloid leukaemia and in GIST patients and
600 mg/day in the accelerated phase or blast crisis of chronic mye-
loid leukaemia. The dosage should be taken once a day in combina-
tion with a meal and water.
Pharmacokinetics
The mean absolute systemic availability of imatinib is about
98% [1]. Imatinib is metabolised by the liver mainly by the cyto-
chrome P450 isoform CYP3A4 that plays a pivotal role in degrada-
tion, where as N-desmethyl imatinib (CGP74588) is the main active
metabolite [2]. The plasma AUC for this metabolite is about 15% of
the AUC of imatinib. Drug elimination is primarily mediated via
the feces [3,4]. The mean elimination half-live of imatinib and N-
demethylimatinib are 18–27 hours and 40–74 hours respectively.
The peak concentrations average are 3340 ng/ml and 781 ng/ml,
and the trough concentrations are 1540 ng/ml and 508 ng/ml re-
spectively [5]. These values were not changed significantly in pa-
tients with end-stage renal disease or in hemodialysis. Dosage ad-
justment is therefore not necessary in patients with renal impair-
ment [6]. Imatinib can also be used even in patients with severely
impaired hepatic function [7]. A 58-year-old patient with end stage
alcoholic liver cirrhosis developed a well-differentiated hepatocel-
lular carcinoma. Because of in vitro sensitivity of the cells to anti-
bodies against c-kit and cytokeratin 7, imatinib was given in a dos-
age of 100 mg bd based on increased transaminases and cholestasis.
After treatment, one year later, the tumour mass had disappeared as
assessed histologically [8].
*Address correspondence to this author at the Department of Oncol-
ogy/Hematology/Immunology/Rheumatology/Pneumology, South West
German Cancer Center, Eberhard Karls University Tübingen, Otfried-
Müller-Strasse 10, 72076 Tübingen, Germany;
E-mail: joerg.hartmann@med.uni-tuebingen.de
Imatinib is generally well tolerated. Besides mild to moderate
hematological toxicity, its non-haematological adverse effects in-
clude fluid retention, edema, nausea, vomiting, diarrhoea, fatigue
and some skin disorders [9,10]. In addition, there have been also
case reports of hepatitis and transient respiratory failure probably
due to central nervous system oedema [11].
Cardiovascular System

It has been suggested that imatinib may have caused severe
heart failure and left ventricular dysfunction in 10 patients with
pre-existing conditions such as hypertension, diabetes mellitus,
and coronary heart disease [12,13]. Experimental studies have
shown that imatinib induces apoptosis in isolated cardiac myo-
cytes. Several trials and a database of six registration trials have
therefore been reviewed.

The Italian Cooperative Study Group: Four consecutive studies
of imatinib therapy in 833 patients with Ph+ CML, demon-
strated during a median of 19–64 months the overall cardiac
mortality rate of 0.3% [14].

The MD Anderson clinical trials experience of imatinib reached
from July 1998 to July 2006 with a median of 5 years follow-up
[15]. In all imatinib protocols, standard research monitoring
procedures were conducted before treatment and on consecutive
regular intervals. Electrocardiography, echocardiography, and
chest radiography were conducted routinely before treatment
and as clinically indicated during follow-up. The eligibility cri-
teria excluded patients with cardiac problems (NYHA classes
III and IV). After reviewing all reported adverse events, par-
ticularly those that could be considered as having a cardiac ori-
gin, 22 patients (1.8%) were identified as having symptoms that
could be attributed to congestive heart failure, of whom 12 had
previously received interferon and three had received anthracy-
clines. Nine patients were included elsewhere [15]. Their me-
dian age was 70 (range, 49–83) years. Median time from the
start of imatinib treatment to cardiac adverse events was 162
days (range 2–2045). Eighteen patients had previously medical
conditions which were closely associated to cardiovascular dis-
ease: Congestive heart failure (n = 6), type 2 diabetes mellitus

1389-2002/09 $55.00+.00 © 2009 Bentham Science Publishers Ltd.

Tyrosine Kinase Inhibitors – A Review on Pharmacology
(n = 6), hypertension (n = 10), coronary artery disease (n = 8),
dysrhythmias (n = 3), and cardiomyopathy (n = 1). Out of 22
patients, 15 underwent echocardiography or multiple gated ac-
quisition (MUGA) scanning at the time of the events: nine of
these 15 patients had a decreased ejection fractions, and six of
these nine patients had significant conditions that predisposed
them to cardiac disease (three had coronary artery disease, two
congestive heart failure, and one a cardiomyopathy). Out of the
22 patients with symptoms of congestive heart failure, 11 con-
tinued taking imatinib with dosage adjustments and manage-
ment of congestive heart failure without further complications.
However, with the host of confounding factors involved in
these patients, the occurrence of congestive heart failure related
to the use of imatinib was reasonably unambiguous in only
seven out of 1276 patients reviewed (0.5%).

The Novartis clinical database comprised 2327 patients from
six registration trials with imatinib monotherapy representing
5595 patient-years of exposure to imatinib mesylate (average
exposure 2.4 years). Twelve cases of congestive heart failure
(0.5%) were considered to be incident cases (with no previous
history of congestive heart failure or left ventricular dysfunc-
tion) with a possible or probable relation to imatinib. If these
cases are related to the 5595 patients-years of imatinib exposure
the incidence of congestive heart failure is only 0.2% per year.

In the largest study reported to date, 1106 patients with newly
diagnosed CML were randomized to either initial therapy with
imatinib or the previous standard treatment of interferon plus
cytosine arabinoside [16]. Both regimens were examined for
cardiac safety according to an analysis of adverse events as de-
scribed above. The incident cases of cardiac failure and left
ventricular dysfunction, possibly or probably related to expo-
sure to the study medication, was 0.04% per year (1 case in
2309 patient-years) for patients taking imatinib versus 0.75%
per year (four cases in 536 patient-years of exposure) in patients
taking interferon-
and cytosine arabinoside.

Imatinib therapy as a cause of congestive heart failure seems to
be rare. Symptoms occur most commonly in elderly patients
with pre-existing cardiac alterations and may often reflect pre-
disposing cardiac compromise compounded by some element of
fluid retention. As a consequence, patients with a previous car-
diac history should be monitored closely and diuretic therapy
should be initiated directly if fluid retention is recognized.
Sensory Systems
Up to 60% of imatinib recipients develop oedema as an adverse
event. In some of these patients, intense eyelid edema can result in
ophthalmologic symptoms, including ptosis, blepharoconjunctivitis,
visual obstruction, or even retinal edema. Inhibition of PDGFR
leads to imbalance of the tension between endothelial cells and their
extracellular matrix. Severe periorbital edema may need direct sur-
gical debulking of excess skin, fat, and edema of the lower eyelids
resulting in an immediate improvement in visual function. In one
case unfortunately there was no recurrence 6 months after surgery
[17].
Metabolism
Retrospective analysis could demonstrate that imatinib caused
hypophosphatemia more often than expected. Hypophosphatemia
was more pronounced in younger patients, who had taken higher
doses of imatinib mesylate. The underlying mechanism may include
reduced activity of PDGFR. Impairment of bone turnover and os-
teomalacia may therefore be expected during imatinib therapy.
Whether phosphate and vitamin D concentrations should be meas-
ured routinely during imatinib therapy, with the aim of prescribing
phosphate if necessary, is a matter of current debate [18]. Phosphate
is also involved in energy balance and ATP generation. The interac-
tion or consequences of phosphate depletion in imatinib treatment is
still not known.
Current Drug Metabolism, 2009, Vol. 10, No. 5 471
Breccia et al. [19] reported on seven diabetic patients receiving
imatinib for Ph+ CML. Three months after initiation of imatinib
therapy complete cytogenetic response of Ph+ CML was demon-
strated in six out of seven patients. Remission was accompanied by
a significant reduction of fasting blood glucose necessitating a re-
duction of antidiabetic treatment. The only non-responders had no
significant change in plasma glucose or antidiabetic medication.
These findings have been confirmed by Veneri et al. [20] who
demonstrated that during imatinib treatment fasting blood glucose
concentrations declined, leading to a consecutive reduction of insu-
lin dosage in these patients. Imatinib may also increase insulin sen-
sitivity even in non-diabetic persons resulting in hypoglycemic
episodes as shown by Haap & Hartmann [21]. Two months after
completion of imatinib treatment, the effect on insulin sensitivity
was reversible in this patient.
Hematologic Side Effects
Myelosuppression can develop during imatinib therapy, proba-
bly due to inhibition of c-kit, a cytokine receptor that is involved in
early hematopoiesis, inhibition of which can result in suppression
of normal progenitors. It has not yet been elucidated why patients
with hypereosinophilic syndrome or atypical chronic myelomono-
cytic leukemia experience imatinib-related neutropenia very rarely
compared with patients with advanced chronic myeloid leukemia.
However, there is evidence that the more severe the myelosuppres-
sion with imatinib, the larger the response, suggesting that this ad-
verse effect may contribute as a prognostic factor. It has therefore
been proposed that imatinib-related myelosuppression may be a
therapeutic effect on Ph+ clones rather than inhibition of normal
hemopoiesis. Whereas empirical interruption of treatment or dosage
modification may affect the outcome in CML, some authors have
suggested the additional use of G-CSF (for example filgrastim 300
micrograms subcutaneously 2 or 3 times a week) in patients who
have myelosuppression at a dosage of 300 mg/day of imatinib [22].
Liver
There have been a few case reports of hepatotoxicity in patients
taking imatinib mesylate, so far exclusively in females. It has been
proposed that high concentrations of imatinib may predispose to an
increased risk of liver damage; however, it is not clear whether
immunological idiosyncrasy (i.e. a hypersusceptibility) or a meta-
bolic disorder is the underlying reason. A 40-year-old woman with
CML in the chronic phase took imatinib mesylate because of resis-
tance to interferon [23]. She achieved a complete clinical remission
after 3 months but the molecular response was incomplete. Six
months later she developed hepatitis without any evidence of active
viral infection. Serum concentrations of imatinib were markedly
raised (8107 ng/ml), although she had stopped taking medication 6
days before. At that stage there was a complete molecular response.
Several weeks later her hepatic function had completely recovered
and she had normal blood counts with normal differential count.
Rechallenge with imatinib therapy was not performed.
Skin
There is some evidence that the severity of skin reactions due to
imatinib is dosage-related within the therapeutic range. Mild forms
are common at a dosage of 200–600 mg/day, whereas severe erup-
tions have been described in patients taking higher doses (600–1000
mg/day) [24]. Re-exposure to higher doses resulted in relapse of
skin eruptions, which highlights the need for adequate dosage re-
duction in affected patients. In case series, imatinib mesylate has
been demonstrated to cause reversible hypopigmentation of the
skin. Hypopigmentation may be dose-related within the therapeutic
range [25,26]. This benign adverse effect occurred within the first
month of treatment. The underlying mechanism may involve a
regulatory disorder in melanocyte development and survival, which
depends on KIT and SCF [2]. A 60-year-old white woman with
GIST took imatinib 400 mg/day for 2 months with lansoprazole 15
mg/day [27]. She developed bilateral palpebral edema with hy-
472 Current Drug Metabolism, 2009, Vol. 10, No. 5 Hartmann et al.

Table 1. Overview of Substance Specific Unwanted Effects

Imatinib Dasatinib Nilotinib Gefitinib Erlotinib Lapatinib Sunitinib Sorafenib Pazopanib

STI571 BMS-354825 AMN-107 ZD1839 OSI-774 GW572016 SU11248 Bay43-9006 GW786034

Glivec Sprycel Tasigna Iressa Tarceva Tycerb Sutent Nexavar N.N.
Standard dosage 400(-800) mg 50-140 mg mg 250(-500) mg (100-)150 mg 175-1800 mg (37.5-)50 mg 400 mg 800 mg
Target competitive competitive competitive competitive competitive competitive competitive allosteric competitive
inhibition inhibition inhibition inhibition inhibition inhibition inhibition inhibition inhibition
ATP-binding ATP-binding ATP-binding ATP-binding ATP-binding ATP-binding ATP-binding ATP-binding
site site site site site site site site
Hematological events
Anemia +++ + + + + ++ +++ + +
Neutropenia ++++ + ++ + + + +++ ++ +
Thrombocytopenia ++++ + ++ + + + ++ ++ +
Nonhematological events
Hypertension + + + + + + + ++ ++
Thrombo- + + + + + + + + +
sis/embolism
Myocardial infark- + + + + + + + + +
tion
Bleeding ++ ++ + + + + + ++ +
Skin rash +++ ++ ++ ++++ +++++ +++ ++ +++ +++
Edema ++++ ++ + + +++ + + + +
Nausea, vomiting +++ + + ++ +++ +++ + ++ ++
Diarrhea +++ ++ + ++++ ++++ +++ +++ +++ +++
Constipation + + + + + + + + +
Muscle cramps +++ + + + ++ + + + +
Bone alterations +++ + + + +++ + + + +
Fatigue +++ + + + +++++ +++ +++ +++ +++
Fever ++ + + + +++ + + + +
Neuropathy + + + + ++ + + ++ +
Liver enzyme +++ + + + ++ ++ + + +++
elevation
Frequency of occurrence of side effects: + < 10%, ++ 10-24%, +++ 25-50%, ++++ 51-75%, +++++ > 75%
Weissinger et al. Onkologe 13:213-226 2007

Table 2. Overview of Therapeutic Targets and Clinical Applications

Imatinib Dasatinib Nilotinib Gefitinib Erlotinib Lapatinib Sunitinib Sorafenib Pazopanib

Targets
Bcr-abl + + +
c-kit + + + + + +
PDGF-R + + + + + +
Flt-3 + +
EGF-R1 + + + +
EGF-R1 +
VEGF-R + + +
Raf1-Kin +
FGFR +
Scope of application
CML + + +
GIST + + + +
ALL + (Ph+) + +
Eosinophilic leukemia +
Tyrosine Kinase Inhibitors – A Review on Pharmacology Current Drug Metabolism, 2009, Vol. 10, No. 5 473

(Table 2) contd….

Imatinib Dasatinib Nilotinib Gefitinib Erlotinib Lapatinib Sunitinib Sorafenib Pazopanib

DFSP1 +
Metast. RCC + + + +
Thyroid carcinoma +
AML +
Gliomas + + +
Breast cancer + + + + +
Cervical carc +
Non-small cell lung + + + + +
Colorectal carinoma + + +
Pancreatic cancer + +
melanoma + +
Prostate cancer +

* DFSP, Dermatofibrosarcoma protuberans; Ph, Phliladelphia chromosome

Table 3. Overview of Pharmacocinetic Properties

Imatinib Dasatinib Nilotinib Gefitinib Erlotinib Lapatinib Sunitinib Sorafenib

STI571 BMS-354825 AMN-107 ZD1839 OSI-774 GW572016 SU11248 Bay43-9006

Glivec Sprycel Tasigna Iressa Tarceva Tycerb Sutent Nexavar
Novartis Bristol-Meyers- Novartis Astra Zeneca Genentech Inc. GlaxoSmith Pfizer Bayer
Squibb Kline
Standard 400(-800) mg 50-140 mg 400(-800) mg 250(-500) mg (100-)150 mg 175-1800 mg (37.5-)50 mg 400 mg
dosage
Target competitive competitive competitive competitive competitive competitive competitive allosteric
inhibition ATP- inhibition ATP- inhibition ATP- inhibition ATP- inhibition ATP- inhibition ATP- inhibition ATP- inhibition
binding site binding site binding site binding site binding site binding site binding site
Application oral oral oral oral oral oral oral oral
C29H 31N7O C22H 26ClN7O2 S C28H 22F 3N7O C22H 24ClFN4O 3 C22H 23N3O 4 C29H 26ClFN4O 4 C22H 27FN 4O2 C21H 16ClF3N 4O3
S
Molecular 493,60 488.01 529,516 446.902 393.436 581.058 398,48 464.825
mass (g·mol1)
Bioavailability 98 14-34
30 60 100 food 60 4.3fold increase 98 29-49
(%) without by
high-fat meal
Plasma protein 95 96 98 90 92-95 99 90-95 99.5
binding (%)
Volume of 347 2505 -- 1400 94-232 -- 2230 --
distribution (l)
Metabolism CYP3A4 CYP3A4 CYP 3A4 CYP3A4 CYP3A4 CYP3A4 CYP3A4 CYP3A4
CYP2D6 CYP2C19 CYP1A2 CYP2C8 UGT1A9
Enzyme inhibi- CYP3A4, CYP3A4 CYP 3A4 2C8 -- -- CYP3A4 -- CYP2C8 2B6
tion 2C9, 2D6 2C9 2D6 CYP2C8 2C9
Enzyme activa- -- -- CYP 2B6 2C8 -- -- -- -- --
tion 2C9
Half live (h) 18-40 5-6 15-24 48 24-36 24 40-80 25–48
Time peak (h) 2-4 0.5-6 -- 3-7 1-7 3-6 6-12 3
Elimination feces 68% feces 85% feces 94% feces 86% feces 83% feces 71% feces 61% feces 77%
urine 13 % urine 4 % unchan. 69% urine 4 % urine 8 % urine 2 % urine 16 % urine 19%
unchan. 20% unchan. 19 % unchan. 1 % unchan. 27 % predominantly
as metabolites

peremic conjunctivae and labial edema. After withdrawal and rein- drawn, the skin toxicity did not progress any further. The authors
troduction of both drugs, she developed generalized skin reactions, suggested that the skin effect may have result from (1) the well-
even at a low dosage of imatinib with concomitant glucocorticoides known drug-related adverse effects of imatinib and lansoprazole on
plus lansoprazole. When imatinib and lansoprazole were with- the skin and (2) inhibition of lansoprazole clearance by imatinib.
474 Current Drug Metabolism, 2009, Vol. 10, No. 5
Drug Interactions
Imatinib is an inhibitor of some cytochrome P450 isozymes,
such as CYP3A4, CYP2C9, and CYP2D6, and may affect the
pharmacokinetics of substrates such as ciclosporin, ketoconazole,
HMG-CoA reductase inhibitors like simvastatin, warfarin, and
some tricyclic antidepressants [28].
Management of Adverse Drug Reactions
Supportive management of common imatinib-related adverse
effects has been described [29]. Severe nausea may require antie-
metic treatment (for example a 5HT3 receptor antagonist or pro-
chlorperazine). Diarrhea can be controlled by loperamide. Rashes
may need topical or systemic steroids. Muscle cramps may need
electrolyte substitution with magnesium and calcium. Bone aches
may be alleviated with coxibs.
DASATINIB
Dasatinib (BMS-354825), a thiazole carboximide derivative, is
structurally related to imatinib. Targeting src family kinases as well
as imatinib-resistant bcr-abl kinase, dasatinib displays activity in
patients with chronic myeloid leukemia or Philadelphia chromo-
some-positive acute lymphoblastic leukemia [30,31].
Although dasatinib has been approved for these indications in a
dosage of 70 mg bid, the search for the optimal dose regimen con-
tinues [32]. Preliminary data suggest that 100 mg once daily (od)
may offer a more favorable benefit to harm balance in patients with
chronic myeloid leukemia resistant to imatinib or in whom imatinib
causes unacceptable adverse effects. Compared with conventional
twice daily dosing, intermittent tyrosine kinase inhibition produces
clinical remissions with improved safety, with the lowest incidence
of pleural effusion (all grades), neutropenia (grades 3–4), and
thrombocytopenia (grades 3–4). In addition, with dasatinib 100 mg
od, dosage reductions were reported less often compared with dos-
age schedules based on 50 mg bd [33], 140 mg/day, or 70 mg bd.
However, in accelerated phase or blast crisis CML, doses of up to
100 mg bid are necessary.
The main adverse effects of dasatinib include grade 3/4 hemato-
logical toxicity (for example neutropenia and thrombocytopenia),
liver abnormalities, diarrhea, headache, peripheral edema, and
hypocalcemia. In addition, pleural effusion is of clinical concern
and may need treatment with diuretics and thoracocentesis or pleu-
rodesis.
Pharmacokinetics
Dasatinib is well absorbed from the gastrointestinal tract [33].
However, its solubility is pH dependent, and the AUC of dasatinib
can be reduced significantly when antacids or famotidine are used
concomitantly (by 55% and 61% respectively). Dasatinib undergoes
extensive metabolism by CYP3A4 and has an active metabolite.
Further enzymes involved in the metabolism of dasatinib include
FMO-3 and UGT isozymes. Exposure to the active metabolite,
which is equipotent with the parent compound, contributes to about
5% of the AUC of dasatinib. Dasatinib and its metabolites are pri-
marily excreted via the feces. The half-life of the parent compound
is 3–5 hours.
Toxicity Profile
Skin
Different efficacy in target tyrosine kinase inhibition or alterna-
tively inhibition of yet another tyrosine kinase by dasatinib may
explain the increased risk of panniculitis with the latter as compared
with imatinib. Two female patients with chronic phase CML, who
had failed to reach a cytogenetic response to imatinib developed
severe panniculitis after exposure to dasatinib (70 mg bd) [34]. In
one patient, withdrawal and reintroduction of dasatinib together
with prednisone (50 mg/day) successfully controlled the pannicu-
litis, whereas the rash was not steroid-sensitive in the second.
Hartmann et al.
Hemorrhage
Dasatinib has been found to be associated with an increased risk
of bleeding, especially from mucosal surfaces. Although major
bleeding events were usually associated with high-grade thrombo-
cytopenia, an aspirin-like effect on platelets may contribute to an
increased risk of hemorrhage with dasatinib. Inhibition of secon-
dary hemostasis could not be found [35].
T-Cell Inhibition
In vitro observations suggest that dasatinib inhibits T-cell pro-
liferation [36]. Whether this effect translates into clinically signifi-
cant problems such as an increased risk of infection or can be util-
ized for novel indications such as immunosuppression remains to be
determined.
NILOTINIB
Nilotinib (AMN 107) is a second generation tyrosine kinase
inhibitor with structural similarity to imatinib. It does not affect src
family kinases at therapeutic doses. Nilotinib is 20–50 times more
potent than imatinib in inhibiting BCR-ABL, which may encourage
its use in patients who are refractory to imatinib [32]. Nilotinib is
generally well tolerated, as has been shown in recent phase II stud-
ies [37,38]. The most frequent grade 3/4 laboratory abnormalities in
316 patients included thrombocytopenia (29%), neutropenia (28%),
and asymptomatic increases in lipase activity (15%). Pleural and
pericardial effusions and pulmonary edema were rare (under 1%).
Growth factors or platelet transfusions were required very rarely.
Pharmacocinetics
If taken with a high fat meal, bioavailability exceeds 80%. Peak
levels are reached after three hours. Half life is approximately 17
hours. Metabolites are not pharmacological active. Nilotinib is a
competitive inhibitor of CYP3A4 as well as 2C8, 2C9 and 2D6.
The most frequent side effects are QT prolongation, hypophos-
phatemia, hyperglycemia, skin rash and myelosupression [39].
GEFITINIB
Gefitinib is an anilinoquinazoline derivative and represents the
first agent that has been introduced as a potent inhibitor of EGFR
tyrosine kinase for the treatment of advanced non-small-cell lung
cancer refractory or resistant to cytotoxic chemotherapy. Case se-
ries have shown significant radiographic regression and improve-
ment of symptoms. A history of never smoking cigarettes and bron-
choalveolar histology are significant predictors of a radiographic
response to gefitinib. In addition, there are higher response rates in
Japanese versus non-Japanese subjects, in those of performance
status 0 to 1, in women, and in those with adenocarcinoma histol-
ogy and prior immunotherapy or hormonal therapy. If several of
these characteristics are present simultaneously, higher response
rates and a longer median survival time with gefitinib, or the struc-
turally related erlotinib, can be expected [40]. The recommended
dose of gefitinib is 250 mg/day given as single-agent as well as in
combination with cytotoxic drugs [41], and 500 mg/day causes
increased toxicity without additional efficacy.
Pharmacokinetics
The mean absolute systemic availability after oral administra-
tion averages 60% [42]. Gefitinib probably crosses the blood-brain
barrier, which may be favorable in patients with metastatic disease
[43]. Its half-life is about 48 hours, and steady-state concentrations
are achieved within 10 days. Hepatic metabolism via CYP3A4 and
biliary excretion are the major routes of elimination, and renal ex-
cretion is of minor importance.
Toxicity Profile
Respiratory
The most serious adverse effect of gefitinib is lung toxicity,
including rapidly progressive dyspnea with a risk of severe hy-
Tyrosine Kinase Inhibitors – A Review on Pharmacology
poxemia and bilateral ground-glass opacities in CT-scans of the
chest.
Out of 110 patients with non-small-cell lung cancer, who re-
ceived gefitinib over 3 months, 12 developed significant lung toxic-
ity and five died from progressive complications, including chronic
pulmonary fibrosis. The mechanism may involve impairment of
epithelial healing, since EGF is needed to regenerate damaged al-
veolar epithelial cells. Thus, any underlying lung damage (for ex-
ample pre-existing pulmonary fibrosis) may predispose to lung
toxicity [44,45]. This needs to be taken into account in lung cancer
patients with a history of smoking [46].
Gastrointestinal
During treatment with gefitinib 250 mg/day about 40% of pa-
tients develop diarrhea grade 2, which can be successfully con-
trolled in most cases by symptomatic treatment with loperamide.
Patients shall be advised to take loperamide 4 mg immediately,
followed by 2 mg after every loose bowel movement (up to a
maximum of 10 mg/day). If the is response inadequate, withdrawal
of gefitinib may be warranted [47].
Skin
Gefitinib-associated skin reactions correlate with an increased
likelihood of radiographic tumor response and symptomatic
improvement, similar to the structurally related erlotinib and the
monoclonal antibody cetuximab. However, durable radiographic
regression and improvement of symptoms have also been observed
in patients with mild forms of rash and diarrhea.
The combination of clindamycin 1% and benzoylperoxide 5%
gel has been used with some success for the treatment of inflamma-
tory pustular lesions. If gel formulations are not well tolerated, oral
minocycline 100 mg bd can be used instead. The roles of topical
retinoids, topical or systemic corticosteroids, or topical pime-
crolimus creams have not been clearly evaluated. In patients with
very dry skin, Eucerin cream, Cetaphil cream, Aquaphor healing
ointment, or Big Balm can be helpful in treating fissures on the
palms and soles [48].
EGFR ligands are cytokines that are excreted by keratinocytes
during wound healing. It is therefore possible that wound healing
may be impaired during the administration of EGFR tyrosine kinase
inhibitors. However, in contrast to some preclinical results, no in-
terference with would healing was seen with gefitinib in a series of
patients, who underwent laparotomy including adhesiolysis [49].
Another patient had unremarkable wound healing after internal
fixation of a pathological fracture of the left forearm [50].
Hair
EGFR tyrosine kinase inhibitors can cause a folliculitis, with a
median time to onset of 7–10 days. Follicular papules and pustules
rarely reach grade 3/4 severity. In contrast to juvenile acne, bacte-
rial cultures of the initial primary lesions are usually negative [48].
The mechanism has not been clearly elucidated but it may involve
disordered regulation of keratinocyte biology and homeostasis of
hair follicles related to EGFR inhibition. Another mechanism may
be the increased expression of p27Kip1 in basal and follicular
keratinocytes and modified chemokine expression, resulting in
exaggerated skin inflammation. Withdrawal usually leads to rapid
improvement and in some cases spontaneous reduction of symp-
toms has been observed in spite of continued treatment [2].
Inhibitors of EGFR tyrosine kinase can change scalp hair, slow
hair growth, and cause frontal alopecia. In contrast, facial hair and
eyelashes can grow progressively, particularly in women. It has
been speculated that modification of the interaction between the
EGFR-dependent and androgen-dependent signalling pathways may
be the underlying mechanism [2].
Nails
Inhibitors of EGFR tyrosine kinase can cause paronychial in-
flammation with symptoms such as erythema, painful lateral fin-
Current Drug Metabolism, 2009, Vol. 10, No. 5 475
gernails or toenails and pyogenic granuloma-like lesions. These can
resolve spontaneously and commonly disappear after treatment is
withdrawn. Topical glucocorticoids, local antiseptics, avoiding
cutting nails too short, and avoiding the use of shoes that are too
tight have been advised to minimize paronychial inflammation [48].
Management of Adverse Drug Reactions
Increased thromboxane B2 and sP-selectin has been observed in
patients taking gefitinib and suggests that gefinitib may have a
platelet-activating effect that might contribute to its substance-
specific side effects. Indeed, in one study, co-administration of
aspirin reduced adverse effects of gefitinib like rash and diarrhea by
more than 50%, while therapeutic efficacy was not affected [50].
ERLOTINIB
Erlotinib is the second inhibitor EGFR tyrosine kinase that has
been approved for the treatment of locally advanced non-small-cell
lung cancer after failure of at least one prior cytotoxic drug regimen
[51]. It has also been approved for the first-line treatment of metas-
tatic pancreatic cancer in combination with gemcitabine [52].
Erlotinib should be taken in a dosage of 150 mg/day on an
empty stomach at least 1 hour before or 2 hours after a meal.
The most common adverse effects of erlotinib include grade 3/4
rashes and diarrhea, which occur in 9% and 6% of patients respec-
tively, and which warrant drug withdrawal in 1% of patients. Sun
protection is generally recommended, because inhibition of EGFR
in the skin potentiates the harmful effects of ultraviolet radiation. In
patients with lower constitutive concentrations of melanin in the
skin, for example Fitzpatrick skin phototypes I and II, higher sensi-
tivity to ultraviolet radiation and a higher probability of more se-
verely graded rash are expected [53]. Withdrawal of erlotinib has
been recommended when signs of new or progressive unexplained
pulmonary symptoms are observed, such as dyspnea, cough, and
fever, in order to reduce the risk of interstitial lung disease.
Pharmacokinetics
The absolute systemic availability of erlotinib averages 59%
and is significantly increased by a meal. Antacids, proton pump
inhibitors, and histamine H2 receptor antagonists impair the absorp-
tion of erlotinib, because its solubility is reduced at pH values ex-
ceeding 5.0. More than 90% of a dose is metabolized in the liver,
primarily by CYP3A4 and CYP1A2. OSI-420, the major metabo-
lite, has antineoplastic activity. Excretion is mainly via the feces.
The half-life averages 36 hours, and steady-state concentrations are
reached within 7–8 days.
Toxicity Profile
Skin
Bullous, blistering and exfoliative skin conditions have been
reported, very rarely toxic epidermal necrolyse. In 42 patients with
either unresectable or metastatic biliary cancer, erlotinib 150
mg/day orally produced mild (grade 1/2) rashes in all those who
responded; three had grade 2/3 rashes, which required dosage re-
ductions [54].
Gastrointestinal
Gastrointestinal perforation including fatalities has also been
reported with its widespread clinical use, particularly in patients
receiving concomitant anti-angogenetic agents, corticosteroids,
NSAIDS, taxanes or who have a history of peptic ulceration or
diverticular disease.
Ocular Disorder
Corneal perforation or ulceration, abnormal eyelash growth,
keratokonjunctivits sicca have been rarely reported.
Drug Interactions
In a small study in patients with gliomas, the median plasma
AUC of erlotinib was significantly reduced by enzyme-inducing
476 Current Drug Metabolism, 2009, Vol. 10, No. 5
antiepileptic drugs, although the dose of erlotinib had been doubled
beforehand from 450 mg/day to 900 mg/day [55]. In contrast, the
AUC of the active metabolite OSI-420 increased about threefold,
which may compensate for the reduction in exposure to the parent
compound. Drug concentrations in the cerebrospinal fluid were 1–
3% of the peak plasma concentrations.
Erlotinib is a potent inhibitor of CYP1A1 and UGT1A1 and a
moderate inhibitor of CYP3A4 and CYP2C8. However, the rele-
vance of these in vitro data to clinical practice has not been eluci-
dated.
LAPATINIB
Lapatinib, a 4-anilinoquinazoline derivative, is the first dual
tyrosine kinase inhibitor. In contrast to erlotinib and gefitinib, it
inhibits both the ErbB1/HER1 (EGFR) tyrosine kinase and the
ErbB2/HER 2 tyrosine kinase simultaneously. It is used in patients
with advanced metastatic breast cancer refractory to anthracyclines
or taxanes in combination with trastuzumab [56]. It is given orally
in a dose of 1.25 g/day on days 1–14 every 21 days) together with
capecitabine (1.0 g/m
bd on days 1–14 every 21 days).
Lapatinib is generally well tolerated. Grade 3 diarrhea is dose-
limiting, whereas adverse effects such as acneiform rash, nausea,
and fatigue are moderate (grades 1–2).
Pharmacokinetics
Lapatinib peak concentrations are reached 3–4 hours after dos-
ing [57]. Absorption is increased about three-fold when taken with
a meal, but this effect may be highly variable depending on compo-
sition and timing of meals. Therefore, administration on an empty
stomach has been recommended, in contrast to the co-administered
capecitabine, which should be taken with food. The half-life of
lapatinib increases significantly from about 11 hours to 24 hours
during repeated administration, probably because of inhibition of
CYP3A4. Lapatinib crosses the blood–brain barrier, which may
help in the treatment of brain metastases, which are of concern in
about one-third of women with ErbB2 over-expression. Elimination
is primarily by hepatic metabolism and biliary excretion; renal ex-
cretion is minor. Recovery of lapatinib in the feces accounts for
about 27% (3–67%) of an oral dose.
Cardiovascular
The incidence of cardiac toxicity with lapatinib appears to be
low; in one study only 37 of 2812 women (1.3%) had a fall in left
ventricular ejection fraction (LVEF) of at least 20% from baseline
[58]. The onset of reduced LVEF occurred within 9 weeks of treat-
ment in 68% of cases and was rarely symptomatic and generally
reversible and non-progressive. The duration of reduction in LVEF
averaged 42 days.
Drug Interactions:
Lapatinib is a substrate of CYP3A4, and successive increases in
dose may be necessary up to 4.5 g/day in patients who take induc-
ing agents such as carbamazepine 200 mg bd, which reduced the
AUC of lapatinib by about 72% [59].
Lapatinib may inhibit the metabolism of other CYP3A4 sub-
strates, including SN38, resulting in a significant increase in AUC
and Cmax [58].
SUNITINIB
Sunitinib (SU 11248) is a multi-targeted tyrosine kinase inhibi-
tor which is highly active in patients with advanced renal cell carci-
noma (RCC) and imatinib-refractory GIST [60]. The recommended
dose is 50 mg/day, in a schedule of 4 weeks on treatment followed
by 2 weeks off [61-64]. An alternative is continuous dosing with
37.5 mg/day.
Hartmann et al.
The most commonly reported grade 3 adverse effects related to
sunitinib include fatigue, stomatitis, hypertension, dermatitis, de-
pigmentation of the hair and skin (probably due to the yellow color
of the drug itself), subungual splinter hemorrhages, bleeding events
(for example epistaxis), and gastrointestinal discomfort, for exam-
ple nausea and diarrhea. Grade 3/4 laboratory abnormalities include
neutropenia, thrombocytopenia, anaemia, and raised plasma lipase
activity. Dosage modifications (for example from 50 to 37.5 or 25
mg/day) were primarily based on severe forms of fatigue or in-
creased amylase and lipase activities [62].
Pharmacokinetics
Oral sunitinib is well absorbed from the gastrointestinal tract.
Drug exposure is slightly increased after food, but administration is
generally feasible with or without food [65].
Sunitinib is mainly metabolized by CYP3A4, producing a ma-
jor metabolite with comparable antineoplastic activity and compris-
ing 23–37% of total exposure. The active metabolite and other
CYP3A4-mediated biotransformation products are mostly excreted
via the feces; the renal route accounts for less than 20% of the dose.
The half-lives of sunitinib and its major metabolite are 40–60 hours
and 80–110 hours respectively. Accumulation of the parent com-
pound and its active metabolite occurred during repeated daily ad-
ministration up to 3- to 4-fold and 7- to 10-fold, respectively.
Steady-state concentrations are commonly achieved after 10–14
days [29,63,66]. In imatinib-resistant GIST continuous daily sunit-
inib in a dose of 37.5 mg/day is an alternative strategy with accept-
able toxicity and sustained effective drug concentrations without
accumulation across cycles [67].
The AUC of sunitinib and total drug exposure correlated sig-
nificantly with the probability of a partial response in cytokine-
refractory patients with renal cell carcinoma and with time to pro-
gression and overall survival, according to pharmacokinetic and
efficacy data from three studies [68]. These data suggest that there
is an association between increased exposure to the active drug in
the plasma and the probability of clinical benefit. In patients with
severe obesity plasma levels can be below the clinical active level
[69].
Drug Interactions
Sunitinib and its major metabolite do not appear to cause clini-
cally important drug–drug interactions. However, the concomitant
use of potent inducers of CYP3A4 (for example rifampicin) or in-
hibitors of CYP3A4 (e.g. ketoconazole) may warrant an increase in
dosage to a maximum of 87.5 mg/day or a dosage reduction to a
minimum of 37.5 mg/day. The concomitant use of St. John’s wort
is generally not recommended because of unpredictable drug con-
centrations [62].
Toxicity Profile
Skin
Skin and hair discoloration is a common problem in up to 30%
of patients. Other dermatological adverse reactions, including hand-
foot syndrome, are observed in up to 20% [70,71].
Gastrointestinal
Every second patient may develop diarrhea and/or nausea asso-
ciated with disorders of taste, loss of appetite, abdominal discom-
fort, and weight loss.
Cardiovascular
The most common cardiovascular adverse reaction is hyperten-
sion, which was observed in more than 25% in patients with renal
cell carcinoma [64] and in 15% of GIST patients [72]. Hypertension
may be severe in up to 10% of patients. Therefore, blood pressure
monitoring is mandatory, and concomitant use of antihypertensive
drugs is recommended if hypertension develops.
Tyrosine Kinase Inhibitors – A Review on Pharmacology
Another concern is heart failure. In a Phase I/II study of sunit-
inib for GIST, 8% of patients were retrospectively identified to
have developed symptoms of heart failure reflecting clinically rele-
vant reduction of left ventricular ejection fraction [73].
Therefore, prospective documentation of cardiovascular pa-
rameters was mandatory in subsequent randomized phase III studies
of sunitinibi in GIST and RCC. Interestingly, a decrease of LVEF
of more than 20% during the study course was found in 2% of
GIST patients and 4% of IFN-refractory mRCC patients receiving
sunitinib as well as in 2% of the placebo controls. Recently, ex-
panded access data for sunitinib in RCC (n=3997) showed a rate of
0.3% of heart failure. Patients at high cardiovascular risk were not
excluded, and arterial hypertension was found in 13.9%. Therefore,
LVEF measurement is recommended at regular intervals under
sunitinib. If a decrease of >20% of the initial value is documented,
dose reduction and short-term control examination is suggested.
Should signs and symptoms of heart failure occur, sunitinib is to be
discontinued immediately.
Prolongation of the QTc interval may occur and can lead to
torsades-de-pointes tachyarrhythmia. Therefore, both baseline and
periodic 12-lead EKGs are recommended. Naturally, electrolyte
imbalances (e.g. potassium, magnesium) should be controlled and
corrected, and sunitinib is relatively contraindicated in patients with
prior QTc prolongation. The addition of other medications that
prolong the QT interval is to be avoided.
Nephrotoxicity
A recently published report from Patel and colleageus described
a preeclampsia-like syndrome characterized by reversible hyperten-
sion and proteinuria induced by the TKI sunitinib and sorafenib in a
case series [74].
It is well known that in the kidney, glomerular podocytes ex-
press VEGF and glomerular endothelial cells express VEGF recep-
tors. Podocyte-specific deletion of a single VEGF allele causes
proteinuria and capillary endotheliosis in rodents, and disrupted
glomerular VEGF signaling is strongly implicated in the pathogene-
sis of human preeclampsia [75-77].
Seven patients developed a preeclampsia-like syndrome charac-
terized by hypertension and proteinuria after starting therapy. Clini-
cally they developed edema, hypertension, proteinuria, and/or hy-
poalbuminemia). New or exacerbated hypertension required on
average two additional antihypertensive medications and occurred
on average 27 weeks after the start of therapy (range, 2–116 weeks).
All seven patients developed proteinuria (average 3.8 g/g, range
1.1–10.4 g/g), with peak urine protein excretion occurring at a me-
dian of 24 weeks. There was no serologic evidence of glomeru-
lonephritis or microangiopathic hemolytic anemia in four patients
tested. After dose reductioned or discontinuation of treatment a
dramatic improvement was found. With 298 patients treated with
sunitinib or sorafenib at the institutions the cumulative crude inci-
dence of renal adverse events was determined by 2.3%. The true
prevalence of TKI-associated renal toxicity is likely higher because
patients were not routinely screened in a systematic manner for new
proteinuria.
The autors recommended that clinicians should be aware of the
challenges of determining the appropriate criteria for withholding
this effective anticancer therapy and should make use of multidisci-
plinary consultative input to decide how best to manage these
treatment-associated toxic effects.
Bleeding
Mild epistaxis is a common adverse event with sunitinib. Grade
3/ 4 hemorrhagia, however, is probably not increased when com-
pared with placebo-treated patients suffering from the same illness.
For example, patients treated for GIST displayed hemorrhagic
events in 17% when treated with placebo vs. 18% when receiving
sunitinib [72]. While interference with VEGFR-2, which is an im-
Current Drug Metabolism, 2009, Vol. 10, No. 5 477
portant endothelial cell maintenance and survival receptor in addi-
tion to mediating angiogenesis, may lead to microvascular leaks
resulting in mild hemorrhagic side effects, the above-mentioned
higher grade bleeding episodes are interpreted to reflect tumor inva-
sion of large vessels rather than pharmakodynamic effects of sunit-
inib [78].
Myelosuppression
Cytopenias of all blood cell lineages has been observed in pa-
tients treated with sunitinib. However, grade3/ 4 neutropenia,
thrombocytopenia, and anemia develops in less than 10% of pa-
tients.
Endocrine
Sunitinib has been related to hypothyroidism. Screening for
signs of hypothyroidism is recommended, with frequent measure-
ments of TSH concentrations every 2–3 months in order to start
levothyroxine in time.
In a prospective, observational cohort study in a tertiary-care
hospital, there were abnormal serum TSH concentrations in 26 out
of 42 patients, who took sunitinib for renal cell carcinoma or GIST.
Persistent primary hypothyroidism, isolated TSH suppression, and
transient mild rises in TSH were found in 36%, 10%, and 17% of
patients respectively. There appears to be a correlation between the
duration of use of sunitinib and suppressed TSH concentrations as
well as a risk of hypothyroidism. Whether sunitinib induces de-
structive thyroiditis through follicular cell apoptosis has not been
fully elucidated [66,79,80].
SORAFENIB
Sorafenib (BAY 43-9006) is a multi-targeted inhibitor of tyro-
sine kinase that inhibits c-RAF and b-RAF kinases as well as
VEGFR-2, VEGFR-3, FLT-3, c-kit, and the PDGFR tyrosine
kinase in vitro. Sorafenib is effective in pretreated renal cell carci-
noma and advanced Child A hepatocellular carcinoma.
The incidence of treatment-related grade 3/4 adverse events in
phase I studies with sorafenib (n = 179) included hand–foot skin
reactions (8%), hypertension (4%), diarrhea (2%), reduced hemo-
globin concentration (3%), and fatigue (5%). There is some evi-
dence that grade 2–3 hand–foot syndrome and/or diarrhea correlates
with the increase of time to progression compared with patients
without such signs of toxicity [81].
Pharmacokinetics
The recommended oral dose, 400 mg bd, should not be taken
with a fat-rich meal, because of reduced absorption by about 38–
49% compared to intake on an empty stomach. Sorafenib is me-
tabolized to some extent by CYP3A4, resulting in a pyridine-N-
oxide derivative with similar antineoplastic activity to the parent
compound. Elimination is primarily via the feces, about 51% of the
dose being excreted as unchanged drug [82].
Toxicity Profile
Cardiovascular
Hypertension is very common in patients taking sorafenib. In a
metaanalysis of nine studies published between January, 2006, and
July, 2007, including a total of 4599 patients with RCC or other
solid tumours, the overall incidence of all-grade and high-grade (ie,
grade 3 or 4) hypertension were 23.4% (95% CI 16.0-32.9%) and
5.7% (2.5-12.6%), respectively. Appropriate monitoring and treat-
ment is strongly recommended to prevent cardiovascular complica-
tions [83].
Tyrosine kinase inhibitors of the VEGF and PDGF receptor
pathways may target the VHL hypoxia-inducible gene pathway,
which results in inhibition of hypoxia-inducible factor (HIF)-
induced gene products. The latter mediate physiological responses
of the myocardium to ischemia, including myocardial remodelling,
peri-infarct vascularization, and vascular permeability.
478 Current Drug Metabolism, 2009, Vol. 10, No. 5 Hartmann et al.

Tyrosine kinase inhibitor-induced inhibition of HIF may be mechanisms of action, drug resistance and to further analyse indi-
associated with more severe myocardial damage than previously vidual pharmacokinetic data in terms of treatment efficacy and
expected. Of 73 patients with advanced renal cell carcinoma and toxicity. Data suggest that a variety of unknown side effects can
normal creatine kinase MB fraction and cardiac troponin T at base- occur which reflects the different mechanisms of action of the
line, 23% had a significant increase in creatine kinase and troponin drugs. Our current understanding of the function is limited – maybe
T after 2–32 weeks, with symptoms in seven [84]. One patient had with the exception of epidermal growth factor receptor (EGFR)
an acute coronary artery occlusion and myocardial infarction. Elec- signaling - and we have no measurements to reliably predict patient
trocardiographic changes and biochemical markers are important being at risk to develop therapeutic side effects. There is still a lot
indicators, and both should be measured regularly irrespective of to learn about the safety profile of TKI despite the fact that some
whether sunitinib or sorafenib is used. drugs have been approved in several indications. This review may
Endocrine provide important information to clinicians who prescribe TKIs to
their patients.
Patients with metastatic renal cell carcinoma commonly de-
velop mild biochemical thyroid function test abnormalities while ACKNOWLEDGEMENTS
taking sorafenib. However, compared with sunitinib, which is asso-
This article is an extended version of a book chapter (Cytostatic
ciated with a high incidence of thyroid dysfunction, making routine
and Cytotoxic Drugs in J.K. Arousou (Ed.) side effects of drugs
monitoring necessary, patients taking sorafenib need thyroid func-
annual 30. Elsevier B.V. 2008). Published with permission.
tion monitoring only if clinically indicated [85].
ABBREVIATIONS
Nephrotoxicity: See Sunitinib
TKIs = Tyrosine kinase inhibitors
Drug Interactions
ATP = Adenosine-5'-triphosphate
Theoretically, important drug interactions can be expected dur-
ing the co-administration of potent CYP3A4 inducing agents (for VEGFR = Vascular endothelial growth factor receptor
example rifamycins, St. John’s wort, phenytoin, carbamazepine) PDGFR = Platelet-derived growth factor receptor
and CYP3A4 inhibitors (for example triazole antifungal drugs). FLT3 = Fms-related tyrosine kinase 3
However, the co-administration of ketoconazole 400 mg/day with
sorafenib 50 mg/day did not result in changes in sorafenib pharma- CML = Chronic myeloid leukaemia
cokinetics, perhaps because sorafenib is a low-clearance drug [86]. GIST = Gastrointestinal stromal tumor
It is also possible that reduced N-oxide formation may be compen- AUC = Area under the curve
sated by a small increase in UGT1A9-mediated glucuronidation.
Therefore, no dose adjustment appears to be warranted during co- Ph+ = Philadelphia chromosome positive
administration of sorafenib with ketoconazole and probably struc- NYHA = New York Heart Association
turally related triazole antifungal drugs. MUGA = Multiple gated acquisition
In vitro, sorafenib inhibits some CYP isozymes, such as BCR-ABL = Bcr-abl fusion protein
CYP2C9, CYP2B6, CYPC8, and some UGT isozymes, such as
HMG-CoA = 3-Hydroxy-3-methylglutaryl-coenzyme A
UGT1A1 and UGT1A9 [85]. Co-administration of sorafenib with
CPT-11, paclitaxel, or propofol is therefore not recommended until c-kit = Stem cell factor receptor
further data are available. SCF = Stem cell factor
Pazopanib 5HT3 = Serotonine
Pazopanib is a potent, selective, broad-spectrum, multi-targeted FMO3 = Flavin containing monooxygenase 3
inhibitor of receptor tyrosine kinases, including VEGFR-1, EGF (R) = Epidermal growth factor (receptor), p27
VEGFR-2, VEGFR-3, PDGFR-/, and c-kit. It is still under clini-
cal investigation. Total disease control in patients with advanced Kip1 = Cyclin-dependent kinase inhibitor 1B
renal cell carcinoma was 82%. The most common adverse events LVEF = Left ventricular ejection fraction
included rises in transaminases, diarrhea, fatigue, nausea, hair de- IFN = Interferon
pigmentation, and hypertension. According to a recent interim
analysis, adverse effects led to drug withdrawal in 5% of patients. TSH = Thyroid-stimulating hormone
Preliminary data suggest additional activity of the drug in ovarian RAF = Serine/threonine kinase
cancer, with a comparable spectrum of adverse effects [87,88]. HIF = Hypoxia-inducible factor
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