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Clin Pharmacol Ther. 2014 Jul;96(1):81-9. doi: 10.1038/clpt.2014.47. Epub 2014 Feb 24.

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

Author information

1
Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands.
2
Department of Medical Oncology, Academic Medical Center, Amsterdam, The Netherlands.
3
Department of Medical Oncology, University Medical Center Utrecht, Utrecht, The Netherlands.
4
Department of Pharmacy and Pharmacology, Slotervaart Hospital, Amsterdam, The Netherlands.
5
Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
6
Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands.
7
Department of Clinical Chemistry, Erasmus MC, Rotterdam, The Netherlands.
8
Australian School of Advanced Medicine, Macquarie University, Sydney, Australia.
9
Department of Medical Oncology and Clinical Pharmacology, Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam, The Netherlands.

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.

PMID:
24566734
DOI:
10.1038/clpt.2014.47
[Indexed for MEDLINE]

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