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CYP2C9 and CYP2C19 Polymorphic Forms Are Related to Increased Indisulam Exposure and Higher Risk of Severe Hematologic Toxicity

Authors' Affiliations: ¹ Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute/Slotervaart Hospital, and ² Department of Medical Oncology, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands; ³ Eisai Ltd., London, United Kingdom; ⁴ Medical Oncology Division, National Cancer Center Hospital, Tokyo, Japan; and ⁵ Department of Biomedical Analysis, Section of Drug Toxicology, Utrecht University, Utrecht, the Netherlands

Requests for reprints: Anthe Zandvliet, Department of Pharmacy and Pharmacology, Slotervaart Hospital, Louwesweg 6, 1066 EC Amsterdam, the Netherlands. Phone: 31-20-512-46-57; Fax: 31-20-512-4753; E-mail: apaza{at}slz.nl.

Purpose: The anticancer agent indisulam is metabolized by the cytochrome P450 of enzymes CYP2C9 and CYP2C19. Polymorphisms of these enzymes may affect the elimination rate of indisulam. Consequently, variant genotypes may be clinically relevant predictors for the risk of developing severe hematologic toxicity. The purposes of this study were to evaluate the effect of genetic variants of CYP2C9 and CYP2C19 on the pharmacokinetics of indisulam and on clinical outcome and to assess the need for pharmacogenetically guided dose adaptation.

Experimental Design: Pharmacogenetic screening of CYP2C polymorphisms was done in 67 patients treated with indisulam. Pharmacokinetic data were analyzed with a population pharmacokinetic model, in which drug elimination was described by a linear and a Michaelis-Menten pathway. The relationships between allelic variants and the elimination pharmacokinetic parameters (CL, V_max, K_m) were tested using nonlinear mixed-effects modeling. Polymorphisms causing a high risk of dose-limiting neutropenia were identified in a simulation study.

Results: The Michaelis-Menten elimination rate (V_max) was decreased by 27% (P < 0.0001) for heterozygous CYP2C9*3 mutants. Heterozygous CYP2C19*2 and CYP2C19*3 mutations reduced the linear elimination rate (CL) by 38% (P < 0.0001). The risk of severe neutropenia was significantly increased by these mutations and dose reductions of 50 to 100 mg/m² per mutated allele may be required to normalize this risk.

Conclusions: CYP2C9*3, CYP2C19*2, and CYP2C19*3 polymorphisms resulted in a reduced elimination rate of indisulam. Screening for these CYP2C polymorphisms and subsequent pharmacogenetically guided dose adaptation may assist in the selection of an optimized initial indisulam dosage.