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

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.

Assessment of ethnic differences in sunitinib outcome between Caucasian and Asian patients with metastatic renal cell carcinoma: a meta-analysis

“…The effect sizes of above-mentioned factors are relatively small compared to the inter-individual variability of pharmacokinetic characteristics of 32.2% and 42.9% in clearance of sunitinib and SU12662 reported by Diekstra et al [55], and even higher variability published by Houk et al (37.9% and 52.2%, respectively) [44].…”

“…It has been assumed that CYP3A5 Ã 3 is linked with higher sunitinib exposure. The potential association has been explored in Caucasian [55] and Asian mRCC patients [56]. However, no clear correlations between CYP3A5 Ã 3 and sunitinib exposure were observed in either population.…”

“…Moreover, a recent retrospective study in 114 Caucasian patients with sunitinib treatment showed that CYP3A4 Ã 22 (rs35599367 C > T) was associated with decreased sunitinib clearance [55]. It has been reported that activity of CYP3A4 enzyme is particularly sensitive to dietary effects [57].…”

Efflux pump ABCB1 single nucleotide polymorphisms and dose reductions in patients with metastatic renal cell carcinoma treated with sunitinib

“…Moreover, on a series of 115 mRCC patients treated with sunitinib, the TT-variant in rs2032582 in ABCB1 and the TT-variant of rs1128503 in ABCB1 were associated with a higher plasmatic sunitinib clearance (p ϭ 0.02 and 0.05, respectively) [18].…”

A decade of pharmacogenomics research on tyrosine kinase inhibitors in metastatic renal cell cancer: a systematic review

“…Consequently, a number of 67 articles underwent full text review and data extraction. Finally, 15 articles were excluded for data extraction because no treatment was evaluated (n = 8), prognostic biomarkers were investigated (n = 5) or these were no original articles but commentaries (n = 2) and using cross-references, we included two additional studies [37,69]. Ultimately, a total of 54 articles was included in our systematic review.…”