Association Analysis of Genetic Polymorphisms in Genes Related to Sunitinib Pharmacokinetics, Specifically Clearance of Sunitinib and SU12662

MHM Diekstra, HJ Klumpen, Martijn Lolkema, H Yu, Jacqueline Kloth, H Gelderblom, Ron van Schaik, H Gurney, JJ Swen, ADR Huitema, N Steeghs, Ron Mathijssen

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Abstract

Interpatient variability in the pharmacokinetics (PK) of sunitinib is high. Single nucleotide polymorphisms (SNPs) in PK candidate genes have been associated with the efficacy and toxicity of sunitinib, but whether these SNPs truly affect the PK of sunitinib remains to be elucidated. This multicenter study involving 114 patients investigated whether these SNPs and haplotypes in genes encoding metabolizing enzymes or efflux transporters are associated with the clearance of sunitinib and its active metabolite SU12662. SNPs were tested as covariates in a population PK model. From univariate analysis, we found that the SNPs in CYP3A4, CYP3A5, and ABCB1 were associated with the clearance of both sunitinib SU12662. In multivariate analysis, CYP3A4*22 was found to be eliminated last with an effect size of -22.5% on clearance. Observed effect sizes are below the interindividual variability in clearance and are therefore too limited to directly individual dosing of sunitinib.
Original languageUndefined/Unknown
Pages (from-to)81-89
Number of pages9
JournalClinical Pharmacology & Therapeutics
Volume96
Issue number1
DOIs
Publication statusPublished - 2014

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