Association analysis of genetic polymorphisms in genes related to sunitinib pharmacokinetics, specifically clearance of sunitinib and SU12662

M. H M Diekstra*, H. J. Klümpen, M. P J K Lolkema, H. Yu, J. S L Kloth, H. Gelderblom, R. H N Van Schaik, H. Gurney, J. J. Swen, A. D R Huitema, N. Steeghs, R. H J Mathijssen

*Corresponding author for this work

    Research output: Contribution to journalArticle

    53 Citations (Scopus)

    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 and 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 guide individual dosing of sunitinib.

    Original languageEnglish
    Pages (from-to)81-89
    Number of pages9
    JournalClinical Pharmacology and Therapeutics
    Volume96
    Issue number1
    DOIs
    Publication statusPublished - Jul 2014

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