Impact of the CYP2C8 *3 polymorphism on the drug-drug interaction between gemfibrozil and pioglitazone

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT •A drug-drug interaction exists between gemfibrozil (CYP2C8 inhibitor) and pioglitazone (CYP2C8 substrate), whereby gemfibrozil increases pioglitazone plasma exposure. Substantial interindividual variability exists in the pharmacokinetic magnitude of this drug-drug interaction. •CYP2C8*3 is associated with increased metabolism and decreased plasma exposure of pioglitazone. •Polymorphisms in CYP metabolizing enzyme genes, namely CYP2C19 and CYP2D6, have been shown to influence the magnitude of inhibitory drug-drug interactions. However, the extent to which CYP2C8 polymorphisms (e.g. CYP2C8*3) affect the interaction between gemfibrozil and pioglitazone is not known. WHAT THIS STUDY ADDS •The CYP2C8*3 allele influences pharmacokinetic variability in the drug-drug interaction between gemfibrozil and pioglitazone. CYP2C8*3 carriers experienced a larger relative increase in pioglitazone plasma exposure following gemfibrozil administration than wild-type homozygotes. •Consideration should be given to the contribution of polymorphic CYP2C8 alleles to interindividual variability in the pharmacokinetic magnitude of CYP2C8-mediated drug-drug interactions. AIM The objective of this study was to determine the extent to which the CYP2C8*3 allele influences pharmacokinetic variability in the drug-drug interaction between gemfibrozil (CYP2C8 inhibitor) and pioglitazone (CYP2C8 substrate). METHODS In this randomized, two phase crossover study, 30 healthy Caucasian subjects were enrolled based on CYP2C8*3 genotype (n= 15, CYP2C8*1/*1; n= 15, CYP2C8*3 carriers). Subjects received a single 15mg dose of pioglitazone or gemfibrozil 600mg every 12h for 4 days with a single 15mg dose of pioglitazone administered on the morning of day 3. A 48h pharmacokinetic study followed each pioglitazone dose and the study phases were separated by a 14 day washout period. RESULTS Gemfibrozil significantly increased mean pioglitazone AUC(0,∞) by 4.3-fold (P < 0.001) and there was interindividual variability in the magnitude of this interaction (range, 1.8- to 12.1-fold). When pioglitazone was administered alone, the mean AUC(0,∞) was 29.7% lower (P= 0.01) in CYP2C8*3 carriers compared with CYP2C8*1 homozygotes. The relative change in pioglitazone plasma exposure following gemfibrozil administration was significantly influenced by CYP2C8 genotype. Specifically, CYP2C8*3 carriers had a 5.2-fold mean increase in pioglitazone AUC(0,∞) compared with a 3.3-fold mean increase in CYP2C8*1 homozygotes (P= 0.02). CONCLUSION CYP2C8*3 is associated with decreased pioglitazone plasma exposure in vivo and significantly influences the pharmacokinetic magnitude of the gemfibrozil-pioglitazone drug-drug interaction. Additional studies are needed to evaluate the impact of CYP2C8 genetics on the pharmacokinetics of other CYP2C8-mediated drug-drug interactions. © 2012 The British Pharmacological Society.