The effects of febuxostat on the pharmacokinetic parameters of rosiglitazone, a CYP2C8 substrate

Abstract

AIMS To determine the effect of febuxostat on cytochrome P450 2C8 (CYP2C8) activity using rosiglitazone as a CYP2C8 substrate. METHODS Healthy subjects received febuxostat 120mg daily (regimenA) or matching placebo (regimenB) for 9 days along with a single oral dose of rosiglitazone 4mg on day5 in a double-blind, randomized, cross-over fashion (≥7day washout between periods). Plasma samples for analysis of the impact of febuxostat on the pharmacokinetics (PK) of rosiglitazone and its metabolite, N-desmethylrosiglitazone, were collected for 120h after co-administration. RESULTS Of the 39 subjects enrolled, 36 completed the study and were included in the PK analyses. Rosiglitazone PK parameters were comparable between regimens A and B. Median time to maximal plasma concentration, mean maximal plasma concentration (C max), area under the concentration-time curve (AUC) from time zero to the last quantifiable concentration (AUC 0-tlqc), AUC from time zero to infinity (AUC 0-∞), and terminal elimination half-life for regimenA were 0.50h, 308.6ngml -1, 1594.9nghml -1, 1616.0nghml -1 and 4.1h, respectively, and for regimenB they were 0.50h, 327.6ngml -1, 1564.5nghml -1, 1584.2nghml -1 and 4.0h, respectively. Point estimates for the ratio of regimenA to regimenB (90% confidence intervals) for rosiglitazone C max, AUC 0-tlqc and AUC 0-∞ central values were 0.94 (0.89-1.00), 1.02 (1.00-1.04) and 1.02 (1.00-1.04), respectively. CONCLUSIONS Co-administration of febuxostat had no effect on rosiglitazone or N-desmethylrosiglitazone PK parameters, suggesting that febuxostat can be given safely with drugs metabolized through CYP2C8. © 2012 Takeda Global Research & Development Center, Inc. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.