CYP2C9 and CYP2C19 polymorphic forms are related to increased indisulam exposure and higher risk of severe hematologic toxicity.
OBJECTIVE
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.


METHODS
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/m(2) 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.
Zandvliet
Anthe S
AS
Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute/Slotervaart Hospital, Amsterdam, the Netherlands. apaza@slz.nl
Huitema
Alwin D R
AD
Copalu
William
W
Yamada
Yasuhide
Y
Tamura
Tomohide
T
Beijnen
Jos H
JH
Schellens
Jan H M
JH
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000633:toxicity*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D065731:Cytochrome P-450 CYP2C19; D065729:Cytochrome P-450 CYP2C9; D005260:Female; D015894:Genome, Human / Q000235:genetics; D006801:Humans; D008099:Liver / Q000187:drug effects*; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics*; D009369:Neoplasms / Q000201:enzymology*; D011110:Polymorphism, Genetic; D012306:Risk; D013449:Sulfonamides / Q000493:pharmacokinetics / Q000633:toxicity*
D000970:Antineoplastic Agents; C439829:N-(3-chloro-7-indolyl)-1,4-benzenedisulphonamide; D013449:Sulfonamides; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19