Application of In Vitro-In Vivo Extrapolation (IVIVE) and Physiologically-based Pharmacokinetic Modeling to Investigate the Impact of the CYP2C8 Polymorphism on Rosiglitazone Exposure

The purpose of this study was to predict the impact of the CYP2C8*3 genotype on rosiglitazone exposure in the absence and presence of trimethoprim. Prior in vitro and in vivo information for rosiglitazone and trimethoprim were collated from the literature. Specifically, data on the frequency of the different allelic forms of CYP2C8 and their metabolic activity for rosiglitazone were incorporated into a physiologically-based pharmacokinetic (PBPK) model within the Simcyp Simulator (v11.1) to predict differences in the
relative exposure of rosiglitazone according to CYP2C8*3 genotype in a virtual population. Following multiple doses of 8 mg rosiglitazone, the predicted mean AUC(0-24) was 37% lower in CYP2C8*3 homozygotes compared with wildtype homozygotes (p< 0.001), which was consistent with the 36 % lower value observed in vivo (p< 0.001) Kirchheiner et al. (Clin Pharmacol Ther 80:657-667, 2006). Predicted median AUC ratios of rosiglitazone in the presence and absence of trimethoprim ranged from 1.35 to 1.66 for ten virtual trials of subjects with the CYP2C8*1/*1 genotype, which included the observed value of 1.42. In subjects with the CYP2C8*1/*3 genotype, the predicted AUC ratios for all trials were higher than the observed value of 1.18 Kirchheiner et al. (Clin Pharmacol Ther 80:657-667, 2006). Investigating the drug interactions in individuals with rare allelic forms of drug metabolizing enzymes is fraught with many practical problems. Current study demonstrates the utility of prior in vitro metabolism data from such allelic forms to predict the relative exposure of a drug as a function of genotype. However, in vitro inhibition data obtained in one allelic variant (e.g. CYP2C8*1) may not be adequate to predict the in vivo interactions in another allele (e.g. CYP2C8*3), since the inhibitory characteristics of perpetrator might be different in each allelic variant in the same way as that of metabolism of the victim drug by such variants of the enzyme.