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The effects of febuxostat on the pharmacokinetic parameters of rosiglitazone, a CYP2C8 substrate
Author(s) -
Naik Himanshu,
Wu Jingtao,
Palmer Robert,
McLean Lachy
Publication year - 2012
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/j.1365-2125.2012.04182.x
Subject(s) - febuxostat , rosiglitazone , pharmacology , cyp2c8 , pharmacokinetics , allopurinol , chemistry , medicine , repaglinide , uric acid , endocrinology , hyperuricemia , cytochrome p450 , cyp2c9 , metabolism , type 2 diabetes , diabetes mellitus , receptor
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Febuxostat is a xanthine oxidase inhibitor approved for lowering serum urate levels in hyperuricaemic gout patients. It is extensively metabolized both by conjugation via uridine diphosphate glucuronosyltransferase enzymes and by oxidation via cytochrome P450 enzymes. WHAT THIS STUDY ADDS • Using rosiglitazone as a CYP2C8 substrate, we have demonstrated that febuxostat does not impede CYP2C8 metabolic activity, because febuxostat had no impact on rosiglitazone pharmacokinetic parameters. We therefore suggest that febuxostat can be safely co‐administered with CYP2C8‐metabolized drugs. 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 (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 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 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.