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

    Research output: Contribution to journalArticleResearchpeer-review

    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.

    LanguageEnglish
    Pages81-89
    Number of pages9
    JournalClinical Pharmacology and Therapeutics
    Volume96
    Issue number1
    DOIs
    Publication statusPublished - 2014

    Fingerprint

    Genetic Polymorphisms
    Pharmacokinetics
    Single Nucleotide Polymorphism
    Cytochrome P-450 CYP3A
    Genes
    Haplotypes
    Multicenter Studies
    SU 12662
    sunitinib
    Multivariate Analysis
    Enzymes
    Population

    Cite this

    Diekstra, M. H. M., Klümpen, H. J., Lolkema, M. P. J. K., Yu, H., Kloth, J. S. L., Gelderblom, H., ... Mathijssen, R. H. J. (2014). Association analysis of genetic polymorphisms in genes related to sunitinib pharmacokinetics, specifically clearance of sunitinib and SU12662. Clinical Pharmacology and Therapeutics, 96(1), 81-89. https://doi.org/10.1038/clpt.2014.47
    Diekstra, M. H M ; Klümpen, H. J. ; Lolkema, M. P J K ; Yu, H. ; Kloth, J. S L ; Gelderblom, H. ; Van Schaik, R. H N ; Gurney, H. ; Swen, J. J. ; Huitema, A. D R ; Steeghs, N. ; Mathijssen, R. H J. / Association analysis of genetic polymorphisms in genes related to sunitinib pharmacokinetics, specifically clearance of sunitinib and SU12662. In: Clinical Pharmacology and Therapeutics. 2014 ; Vol. 96, No. 1. pp. 81-89.
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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 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.",
    author = "Diekstra, {M. H M} and Kl{\"u}mpen, {H. J.} and Lolkema, {M. P J K} and H. Yu and Kloth, {J. S L} and H. Gelderblom and {Van Schaik}, {R. H N} and H. Gurney and Swen, {J. J.} and Huitema, {A. D R} and N. Steeghs and Mathijssen, {R. H J}",
    year = "2014",
    doi = "10.1038/clpt.2014.47",
    language = "English",
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    Diekstra, MHM, Klümpen, HJ, Lolkema, MPJK, Yu, H, Kloth, JSL, Gelderblom, H, Van Schaik, RHN, Gurney, H, Swen, JJ, Huitema, ADR, Steeghs, N & Mathijssen, RHJ 2014, 'Association analysis of genetic polymorphisms in genes related to sunitinib pharmacokinetics, specifically clearance of sunitinib and SU12662', Clinical Pharmacology and Therapeutics, vol. 96, no. 1, pp. 81-89. https://doi.org/10.1038/clpt.2014.47

    Association analysis of genetic polymorphisms in genes related to sunitinib pharmacokinetics, specifically clearance of sunitinib and SU12662. / Diekstra, M. H M; Klümpen, H. J.; Lolkema, M. P J K; Yu, H.; Kloth, J. S L; Gelderblom, H.; Van Schaik, R. H N; Gurney, H.; Swen, J. J.; Huitema, A. D R; Steeghs, N.; Mathijssen, R. H J.

    In: Clinical Pharmacology and Therapeutics, Vol. 96, No. 1, 2014, p. 81-89.

    Research output: Contribution to journalArticleResearchpeer-review

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    AU - Diekstra, M. H M

    AU - Klümpen, H. J.

    AU - Lolkema, M. P J K

    AU - Yu, H.

    AU - Kloth, J. S L

    AU - Gelderblom, H.

    AU - Van Schaik, R. H N

    AU - Gurney, H.

    AU - Swen, J. J.

    AU - Huitema, A. D R

    AU - Steeghs, N.

    AU - Mathijssen, R. H J

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