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Cisplatin Dosing Question

by Tunggul Adi Purwonugroho

OUTLINE
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Overview of Cisplatin
BSA-based dosing
AUC-based dosing
Alternative dosing method for Cisplatin

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Pharmacotherapy , A Pathophysiology Approach 7th edition,


Di Piro, JT, et al

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Overview of Cisplatin
Cisplatin (cis-diaminedichloroplatinum) is a frequently

applied agent with a broad spectrum of activity against


solid tumors, including testicular, ovarian, bladder,
lung, and head and neck cancers (de Jongh, 2001)

Main adducts formed in the


interaction of cisplatin with DNA.
(a) interstrand cross-link
(b) 1,2-intrastrand cross-link.
(c) 1,3-intrastrand cross-link.
(d) protein-DNA cross-link
(Gonzales, 2001)

Overview of Cisplatin
The short-term, dose-dependent toxicities are

myelosuppression, nausea and vomiting, nephropathy,


and neuropathy. The long-term toxicities are
ototoxicity, reduced fertility, persistent neuropathy,
and secondary malignancies. (Salas, 2006)
With the use of optimal hydration measures, including
supplementation of potassium and magnesium, it
decreasedthe incidence of nephrotoxicity. (de Jongh,
2001)

Variablity on anticancer drugs


Anticancer drugs can have considerable

interindividual pharmacokinetic variability, which,


given the narrow therapeutic index of these drugs,
results in unpredictable clinical effects. (Undevia, 2005)

(Felici, 2002)

Variablity on anticancer drugs


Variability originates

from a combination of
physiologic variables
and intrinsic
characteristics, such as
genetic components, as
well as environmental
factors, which together
determine a patients
phenotype. (Loos,
2006)
(Kaestner, 2006a)

BSA-dosing
In 1883, it was discovered that small animals utilised

relatively more oxygen and produced relatively more heat


than larger animals. These findings could be explained
because smaller animals have relatively larger surface areas
per unit mass, when compared with larger animals.
(Kaestner, 2006a)
These observations were confirmed and applied to
humans, giving rise to the practice of expressing human
basal metabolism in terms of BSA rather than body weight
(BW) to eliminate pharmacokinetic and subsequent
pharmacodynamic variability between patients. (Loos,
2006)

BSA-dosing
The most commonly used of BSA formula is that derived by

DuBois and DuBois , in 1916, studying only 9 patients (BSA


(m2)=weight (kg)0.425 x height (cm)0.7250 x 0.007184) (Felici, 2002)
Retrospectively assessed the pharmacokinetics of 33
investigational agents tested in phase I trials from 1991 through
2001, as a function of body surface area in 1650 adult cancer
patients. BSA-based dosing was statistically significantly
associated with a reduction in interpatient variability in drug
clearance for only five of the 33 agents: docosahexaenoic acid
(DHA)paclitaxel, 5-fluorouracil/eniluracil, paclitaxel,
temozolomide, and troxacitabine. (Baker, 2002)

BSA-dosing of Cisplatin
de Jongh et al, found that the coefficient of variation for

cisplatin CL expressed in absolute measures or relative to


BSA were both in the same order (23.6% v 25.6%) and that
BSA was poorly related to unbound cisplatin CL. (de Jongh,
2001)
On the other hand, it is noteworthy that the interindividual
variability in BSA of the patients was only 10.4%, indicating
that an effect of BSA on cisplatin CL was measurable but not
highly contributory. This strongly suggests that other
(unknown) factors than BSA could be considered more
important predictors of CL and AUC. (de Jongh, 2001)

BSA-dosing of Cisplatin
Evaluation of an Alternate Dosing Strategy for

Cisplatin in Patients With Extreme Body Surface Area


Values.
Results: the clearance of unbound platinum in patients
with a BSA value 1.65 m2 was 16% slower (P<.001),
while an 18% faster clearance (P<.001) was observed in
patients with a BSA value 2.05 m2
Recommendation: Unless better predictors for
platinum clearance are identified, fixed-dose regimens
per BSA cluster ( 1.65 m2; 1.66 m2 to 2.04 m2; 2.05
m2) are recommended.
(Loos, 2006)

Dose recommendation (Loos, 2006)

Several cisplatin dosing approach


Stu
dy

Type of
cancer

Subject

Surrogate
index

Related to
BSA or not

Other related
factor

Free or
bound

Alternative
approach

Advanced
solid tumor

268 adult
patients

CL

Weak

Unknown

Free

Advanced
solid tumor

25 +268
adult
patients

CL

For extreme
BSA,
significant

Unknown

Free

Advanced
solid tumor

285 adult
patients

CL

Significant

Age, sex, renal


dysfunction
are not
associated

Free

Population
pharmacokine
tics modelling

Osteosarco
ma and
neuroblasto
ma

21 children
patients

AUC

Weak

Unknown

Free

1.
2.
3.
4.

De Jongh, 2001
Loos, 2006
De Jongh, 2004
Peng, 1997

Several cisplatin dosing approach


Stu
dy

Type of
cancer

Subject

Surrogate
index

Related to
BSA or not

Other related
factor

Free
or
total

Alternative
approach

Lung cancer

27 adult
patients

CL

Not studied

Not studied

Total

Model of
cisplatin dose
adjusment using
Bayesian
analysis

Solid tumor

12
children
patients

Cmax in plasma
and urine

Not studied

Not studied

Free

Not studied

Unknown

19
children
patients

AUC

Not related

AUC=[(weight0.7)
(Cmax X t1/20.5)]

Free

Not studied

Head, neck,
ang other
solid tumor

18 adult
patients

CL

Not studied

Not studied

Total

Model of
cisplatin dose
adjusment using
Bayesian
analysis

5. Desoize, 1996
6. Erdlenbruch, 2001, Abstract
7. Goodisman, 2006
8. Monjanel-Mouterde, 2003

Several cisplatin dosing approach


Stu
dy

Type of
cancer

Subject

Surrogate
index

Related to
BSA or not

Other related
factor

Free
or
total

Alternative
approach

Not
mentioned

43 adult
patients

Cl

Significantly
related

Renal
insufficiency

Free

Bootstrap PK
modelling

10

Not
mentioned

32 adult
patients

Cl

Significantly
related

Not studied

Free
and
total

Bootstrap PK
modelling

11

Testicular

19 adult
patients

Cl

Weak

Therapeutic
course number

Total

Bootstrap PK
modelling

12

Head, neck,

18 adult
patients

Level of Pt
DNA adducts
in peripheral
WBC and AUC

Not studied

Not studied

Free

Adaptive
intrapatient
dose escalation

9. Urien, 2004
10. Urien, 2005
11. Salas, 2006
12. Schellens, 2001

AUC-based dosing in Carboplatin


Carboplatin is a drug for which non-BSA-based dosing

has been well established.


The widely adopted Calvert formula uses the
correlation between renal and total body clearance of
carboplatin and GFR to obtain a dose from a target
AUC.
Dose (mg) = AUC x (GFR + 25)
Target AUCs are normally recommended as 5 and 7
mg/ml x min for previously treated and untreated
individuals, respectively, based on the relationship for
AUC with therapeutic and toxic effects
(Kaestner, 2006b)

AUC-based dosing in Carboplatin


Sources of inaccuracy:
The Calvert formula was developed using GFR as measured by the
, but some use
to
measure the creatinine clearance as an alternative, and it is well
recognized that these can be inaccurate. The majority of clinical
investigators and physicians
,
the GFR by using formulas such as Jelliffe or Cockcroft-Gault and
then insert these numbers into the Calvert formula, even though
the original Calvert calculations were not derived from such
sources. A calculated GFR is not the same as one that is measured,
and creatinine clearance can exceed GFR by 10% to 40%. The
commonly used formulas such as Jelliffe, Cockcroft-Gault, or
Chatelut use serum creatinine;
for measuring serum creatinine (enzymatic or Jaffe) give different
results and are an additional source of discrepancy. (Gore, 2003)

Why it is different (carboplatin and cisplatin?


Eighty to eighty-eight per cent of platinum are
, as for
cisplatin, whereas carboplatin is less reactive.
Cisplatin active metabolites, i.e. monoaquo platin and dach-platin quickly
react with small proteins with sulfhydryl groups, such as glutathione, cysteine

and methionine, and then with high molecular weight proteins, such as
albumin and gammaglobulins through covalent link. Thus, their terminal half
lives are long, about ten days, and, both total and ultrafiltrable platinum
progressively accumulate in plasma. On the other hand, carboplatin is more
stable, less bound to proteins and is largely excreted unchanged in urine.
Cisplatin was excreted by an active renal secretory mechanism whilst
carboplatin was eliminated by glomerular filtration alone.
Erythrocytes represent an important deep compartment, for cisplatin. On the
contrary, carboplatin is quickly extruded from erythrocytes.
Plasma clearance is correlated to creatinine clearance, but only carboplatin
dosage can be individually adjusted, based on creatinine clearance
measurement, to its simple renal excretion, due to exclusive glomerular
filtration, and after Calvert's, Egorin's and Chatelut's population kinetics
studies.
, combining reabsorption
and secretion processes.
(Boisdron-Celle, 2001, Abstract) and (Siddik, 1987, Abstract)

General principles to calculate the dose of


anticancer drugs

(Gurney, 2002)

General principles to calculate the dose of


anticancer drugs

(Gurney, 2002)

References
Baker, S. D., Verweij, J., Rowinsky, E. K., Donehower, R. C., Schellens, J. H., Grochow, L.
B., et al. (2002). Role of body surface area in dosing of investigational anticancer agents in
adults, 1991-2001. J Natl Cancer Inst, 94(24), 1883-1888.

Boisdron-Celle, M., Lebouil, A., Allain, P., & Gamelin, E. (2001). [Pharmacokinetic
properties of platinium derivatives]. Bull Cancer, 88 Spec No, S14-19. Abstract.
de Jongh, F. E., Gallo, J. M., Shen, M., Verweij, J., & Sparreboom, A. (2004). Population
pharmacokinetics of cisplatin in adult cancer patients. Cancer Chemotherapy and
Pharmacology, 54(2), 105-112.
de Jongh, F. E., Verweij, J., Loos, W. J., de Wit, R., de Jonge, M. J. A., Planting, A. S. T., et
al. (2001). Body-Surface Area-Based Dosing Does Not Increase Accuracy of Predicting
Cisplatin Exposure. Journal of Clinical Oncology, vol. 19, 3733-3739.
Desoize, B., Berthiot, G., Manot, L., Coninx, P., & Dumont, P. (1996). Evaluation of a
prediction model of cisplatin dose based on total platinum plasma concentration.
European Journal of Cancer, 32(10), 1734-1738.

Erdlenbruch, B., Nier, M., Kern, W., Hiddemann, W., Pekrun, A., & Lakomek, M. (2001).
Pharmacokinetics of cisplatin and relation to nephrotoxicity in paediatric patients. Eur J
Clin Pharmacol, 57(5), 393-402. Abstract.
Felici, A., Verweij, J., & Sparreboom, A. (2002). Dosing strategies for anticancer drugs: the
good, the bad and body-surface area. European Journal of Cancer, 38(13), 1677-1684.

References
Gonzalez, V. M., Fuertes, M. A., Alonso, C., & Perez, J. M. (2001). Is cisplatin

induced cell death always produced by apoptosis? Mol Pharmacol, 59(4), 657663.
Goodisman, J., & Souid, A. K. (2006). Constancy in integrated cisplatin plasma
concentrations among pediatric patients. J Clin Pharmacol, 46(4), 443-448.
Gore, M. (2003). Carboplatin Equals Cisplatin: But How Do I Prescribe It?
Journal of Clinical Oncology, vol. 21, 3183-3185.
Gurney, H. (2002). How to calculate the dose of chemotherapy. Br J Cancer,
86(8), 1297-1302.
Kaestner, S. A., & Sewell, G. J. (2007a). Chemotherapy Dosing Part I: Scientific
Basis for Current Practice and Use of Body Surface Area. Clinical Oncology,
19(1), 23-37.
Kaestner, S. A., & Sewell, G. J. (2007b). Chemotherapy Dosing Part II:
Alternative Approaches and Future Prospects. Clinical Oncology, 19(2), 99-107.
Loos, W. J., de Jongh, F. E., Sparreboom, A., de Wit, R., van Boven-van
Zomeren, D. M., Stoter, G., et al. (2006). Evaluation of an Alternate Dosing
Strategy for Cisplatin in Patients With Extreme Body Surface Area Values.
Journal of Clinical Oncology, vol. 24, 1499-1506.

References
Monjanel-Mouterde, S., Ciccolini, J., Bagarry, D., Zonta-David, M., Duffaud, F., Favre, R.,
et al. (2003). Population pharmacokinetics of cisplatin after 120-h infusion: application to
routine adaptive control with feedback. Journal of Clinical Pharmacy and Therapeutics,
vol. 28, 109-116.

Peng, B., English, M. W., Boddy, A. V., Price, L., Wyllie, R., Pearson, A. D. J., et al. (1997).
Cisplatin pharmacokinetics in children with cancer. European Journal of Cancer, 33(11),
1823-1828.
Salas, S., Mercier, C., Ciccolini, J., Pourroy, B., Fanciullino, R., Tranchand, B., et al. (2006).
Therapeutic drug monitoring for dose individualization of Cisplatin in testicular cancer
patients based upon total platinum measurement in plasma. Ther Drug Monit, 28(4),
532-539.
Schellens, J. H., Planting, A. S., Ma, J., Maliepaard, M., de Vos, A., de Boer Dennert, M., et
al. (2001). Adaptive intrapatient dose escalation of cisplatin in patients with advanced
head and neck cancer. Anticancer Drugs, 12(8), 667-675.
Siddik, Z. H., Newell, D. R., Boxall, F. E., & Harrap, K. R. (1987). The comparative
pharmacokinetics of carboplatin and cisplatin in mice and rats. Biochem Pharmacol,
36(12), 1925-1932. Abstract.
Urien, S., Brain, E., Bugat, R., Pivot, X., Lochon, I., Van, M.-L. V., et al. (2005).
Pharmacokinetics of platinum after oral or intravenous cisplatin: a phase 1 study in 32
adult patients. Cancer Chemotherapy and Pharmacology, 55(1), 55-60.
Urien, S., & Lokiec, F. (2004). Population pharmacokinetics of total and unbound plasma
cisplatin in adult patients. Br J Clin Pharmacol, 57(6), 756-763.

Thank you for the attention