Meta-analysis of contribution of genetic polymorphisms in drug-metabolizing enzymes or transporters to axitinib pharmacokinetics

Abstract

Purpose Axitinib, an orally administered inhibitor of vascular endothelial growth factor 1, 2 and 3, is primarily metabolized by cytochrome P450 (CYP) 3A4/5 but is also a substrate for CYP1A2, CYP2C19, UDP-glucuronosyltransferase (UGT) 1A1 and the drug transporters P-glycoprotein (encoded by the ABCB1 gene) and OATP1B1 (encoded by SLC01B1). The potential contribution of polymorphisms in genes encoding these enzymes and transporters to axitinib pharmacokinetic variability was assessed. Methods A fixed effects meta-analysis was performed using data pooled from 11 healthy volunteer clinical pharmacology trials to investigate the potential association between axitinib exposure and major polymorphisms in these genes following a 5-mg dose of axitinib.Results Up to 15 variant alleles were evaluated and up to 315 healthy volunteers per polymorphism were assayed. None of the polymorphisms analysed was a statistically significant predictor of axitinib pharmacokinetic variability. Amongst genotypes and inferred phenotypes, CYP2C19 genotype and the ABCB1 (G2677T/A) polymorphism were the closest to statistical significance in influencing axitinib pharmacokinetic variability after multiple-testing adjustment. However, no enzyme or transporter genotype/inferred phenotype contributed >5% to the overall pharmacokinetic variability of axitinib. Conclusions No statistically significant associations between the specific polymorphisms analysed and axitinib plasma exposure were observed, suggesting that genotype-or inferred phenotype-based adjustment of axitinib dose in individual subjects is not warranted.

In Vitro Characterization of Axitinib Interactions with Human Efflux and Hepatic Uptake Transporters: Implications for Disposition and Drug Interactions

“…Because axitinib showed some OATP1B1 substrate activity, this observation led us to the hypothesis that an inactive phenotypic variant could be a factor in clinical PK variability. However, no significant association between the SLCO1B1 (T521C) genetic polymorphism and variability in axitinib plasma exposure was noted in a pooled analysis of 11 healthy volunteer studies during early clinical trials (Brennan et al, 2012). Thus, it is likely that the observed high permeability of axitinib overrides any potential differences in active hepatic uptake that could be exhibited by phenotypic variants of these transporters.…”

In Vitro Kinetic Characterization of Axitinib Metabolism

“…When comparing the data from the formation of the sulfoxide metabolite, a similar contribution of CYP3A5 (18%) was noted to that of the parent loss method. Thus, it was shown CYP3A4 contributed to the majority (;66%) of both parent loss and sulfoxide metabolite formation, which has also been supported by clinical observations on the relevance of CYP3A5 polymorphism in axitinib clearance (Brennan et al, 2012;Pithavala et al, 2015). Together these in vitro results suggest an insignificant clinical contribution (,30% contribution) of CYP3A5 to the in vivo metabolic clearance of axitinib (Tseng et al, 2014), which if conducted a priori would not justify clinical investigation.…”

“…Therefore, genotyping of drug metabolizing enzymes during clinical studies in which axitinib was administered to healthy volunteers were conducted. Clinical results indicated no clear correlation of CYP3A5 polymorphisms with variability in axitinib pharmacokinetics (Brennan et al, 2012), indicating CYP3A5 may have a rather small clinical contribution to overall oral clearance. Recently, in vitro tools to confirm or refute the contribution of CYP3A5 have been made available via the use of CYP3cide, a specific CYP3A4 inhibitor (Walsky et al, 2012b).…”

Axitinib in the treatment of renal cell carcinoma: patient selection and perspectives

“…48,56 However, a meta-analysis of eleven studies evaluating SNPs in genes encoding major enzymes involved in axitinib metabolism did not demonstrate any significant association with axitinib plasma exposure. 56 In addition, an analysis of blood samples from 305 patients from the AXIS trial evaluated the association between germline SNPs …”