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CYP2C9 and CYP2C19 polymorphic forms are related to increased indisulam exposure and higher risk of severe

Anthe S Zandvliet1, Alwin D R Huitema, William Copalu

  • 1Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute/Slotervaart Hospital, Amsterdam, the Netherlands. apaza@slz.nl

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|May 17, 2007
PubMed
Abstract

Insights

Genetic variants in CYP2C9 and CYP2C19 enzymes significantly impact indisulam metabolism, increasing the risk of severe neutropenia. Pharmacogenetic screening and dose adjustments are crucial for optimizing indisulam therapy.

Area of Science:

  • Pharmacogenomics
  • Oncology
  • Drug Metabolism

Background:

  • Indisulam, an anticancer agent, is metabolized by cytochrome P450 enzymes CYP2C9 and CYP2C19.
  • Genetic variations (polymorphisms) in these enzymes can alter indisulam's elimination rate.
  • These variations may predict the risk of severe hematologic toxicity in patients.

Purpose of the Study:

  • To investigate the impact of CYP2C9 and CYP2C19 genetic variants on indisulam pharmacokinetics.
  • To evaluate the relationship between these genetic variants and clinical outcomes, specifically hematologic toxicity.
  • To determine the necessity of pharmacogenetically guided indisulam dose adaptation.

Main Methods:

  • Pharmacogenetic screening for CYP2C polymorphisms in 67 patients receiving indisulam.
  • Population pharmacokinetic modeling to describe indisulam elimination (linear and Michaelis-Menten pathways).
  • Nonlinear mixed-effects modeling to assess the relationship between allelic variants and pharmacokinetic parameters (CL, Vmax, Km).
  • Simulation study to identify polymorphisms linked to dose-limiting neutropenia.

Main Results:

  • Heterozygous CYP2C9*3 mutants showed a 27% decrease in Michaelis-Menten elimination rate (Vmax).
  • Heterozygous CYP2C19*2 and CYP2C19*3 mutations reduced the linear elimination rate (CL) by 38%.
  • These mutations significantly increased the risk of severe neutropenia, suggesting potential dose reductions of 50-100 mg/m² per mutated allele.

Conclusions:

  • CYP2C9*3, CYP2C19*2, and CYP2C19*3 polymorphisms lead to reduced indisulam elimination.
  • Screening for these CYP2C polymorphisms can guide dose adaptation.
  • Pharmacogenetically informed dosing may optimize initial indisulam therapy and mitigate toxicity.

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