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Drug Information

Drug Information . Cisplatin Dosing Question by Tunggul Adi Purwonugroho. Question. Does AUC based cisplatin dosing provide more advantage(s) than (or over) BSA based dosing, and how to do that ?. OUTLINE. Searching Method Content Overview of Cisplatin BSA-based dosing

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Drug Information

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  1. Drug Information Cisplatin Dosing Question by TunggulAdiPurwonugroho

  2. Question Does AUC based cisplatin dosing provide more advantage(s) than (or over) BSA based dosing, and how to do that ?

  3. OUTLINE Searching Method Content • Overview of Cisplatin • BSA-based dosing • AUC-based dosing • Alternative dosing method for Cisplatin

  4. Searching method PUBMED: SCIENCE DIRECT: TEXTBOOK: Pharmacotherapy , A Pathophysiology Approach 7th edition, Di Piro, JT, et al

  5. Retrieving information processess

  6. 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)

  7. 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)

  8. 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)

  9. 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 patient’s phenotype. (Loos, 2006) (Kaestner, 2006a)

  10. 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)

  11. 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 xheight (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)

  12. 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 waspoorly 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)

  13. 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)

  14. Dose recommendation (Loos, 2006)

  15. Several cisplatin dosing approach De Jongh, 2001 Loos, 2006 De Jongh, 2004 Peng, 1997

  16. Several cisplatin dosing approach 5. Desoize, 1996 6. Erdlenbruch, 2001, Abstract 7. Goodisman, 2006 8. Monjanel-Mouterde, 2003

  17. Several cisplatin dosing approach 9. Urien, 2004 10. Urien, 2005 11. Salas, 2006 12. Schellens, 2001

  18. 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)

  19. AUC-based dosing in Carboplatin • Sources of inaccuracy: The Calvert formula was developed using GFR as measured by the 51Cr-EDTA method, but some use 24-hour urine collections 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 calculate, rather than measure, 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; differences in the methodology for measuring serum creatinine (enzymatic or Jaffe) give different results and are an additional source of discrepancy. (Gore, 2003)

  20. Why it is different (carboplatin and cisplatin? • Eighty to eighty-eight per cent of platinum are bound to proteins, as for cisplatin, whereas carboplatin is less reactive. • Cisplatin active metabolites, i.e. monoaquoplatin 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. Cisplatin renal excretion is more complex, combining reabsorption and secretion processes. (Boisdron-Celle, 2001, Abstract) and (Siddik, 1987, Abstract)

  21. General principles to calculate the dose of anticancer drugs (Gurney, 2002)

  22. General principles to calculate the dose of anticancer drugs (Gurney, 2002)

  23. Conclusion Does AUC based cisplatin dosing provide more advantage(s) than (or over) BSA based dosing, and how to do that ? In fact that there are some conflicting data relating with AUC based cisplatin dosing, and the lack data of established alternative approach  conducted the population PK to know the factors that contribute in the AUC cisplatin in particular patient (type of cancer, age, concomitant drug) is one of alternative way to overcoming the variability in the BSA-based dosing of cisplatin. Before it is available, general principles to calculate the dose of anticancer drug should be applied in line with conducting the available protocol.

  24. 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 ClinPharmacol, 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.

  25. 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), 657-663. • Goodisman, J., & Souid, A. K. (2006). Constancy in integrated cisplatin plasma concentrations among pediatric patients. J ClinPharmacol, 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.

  26. 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. BiochemPharmacol, 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 ClinPharmacol, 57(6), 756-763.

  27. Thank you for the attention

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