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

AIMS To determine the effect of febuxostat on cytochrome P450 2C8 (CYP2C8) activity using rosiglitazone as a CYP2C8 substrate. METHODS Healthy subjects received febuxostat 120 mg daily (regimen A) or matching placebo (regimen B) for 9 days along with a single oral dose of rosiglitazone 4 mg on day 5 in a double-blind, randomized, cross-over fashion (=7 day 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 120 h 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 (Cmax), area under the concentration-time curve (AUC) from time zero to the last quantifiable concentration (AUC0tlqc), AUC from time zero to infinity (AUC08), and terminal elimination half-life for regimen A were 0.50 h, 308.6 ng ml-1, 1594.9 ng h ml-1, 1616.0 ng h ml-1 and 4.1 h, respectively, and for regimen B they were 0.50 h, 327.6 ng ml-1, 1564.5 ng h ml-1, 1584.2 ng h ml-1 and 4.0 h, respectively. Point estimates for the ratio of regimen A to regimen B (90% confidence intervals) for rosiglitazone Cmax, AUC0tlqc and AUC08 central values were 0.94 (0.891.00), 1.02 (1.001.04) and 1.02 (1.001.04), 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.