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Effect of hydrochlorothiazide on the pharmacokinetics and pharmacodynamics of febuxostat, a non‐purine selective inhibitor of xanthine oxidase
Author(s) -
Grabowski Brian,
Khosravan Reza,
Wu JingTao,
Vernillet Laurent,
Lademacher Christopher
Publication year - 2010
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.1365-2125.2010.03667.x
Subject(s) - febuxostat , hydrochlorothiazide , pharmacology , pharmacodynamics , xanthine oxidase , medicine , gout , xanthine oxidase inhibitor , uric acid , pharmacokinetics , hyperuricemia , chemistry , biochemistry , blood pressure , enzyme
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Hyperuricaemia and gout frequently coexist with cardiovascular disorders such as hypertension and heart failure. The use of diuretics has been re‐established as a first‐line treatment for patients with hypertension and the effects of diuretics on serum uric acid may diminish the urate‐lowering effects of febuxostat, a novel, potent, non‐purine selective inhibitor of xanthine oxidase. WHAT THIS STUDY ADDS • Co‐administration of febuxostat 80 mg and hydrochlorothiazide 50 mg had no effect on the pharmacokinetics and did not have a clinically significant effect on the pharmacodynamics of febuxostat. Dose adjustment for febuxostat is not necessary when it is administered with hydrochlorothiazide. AIM This study examined the effect of co‐administration of febuxostat, an investigational urate lowering therapy, and hydrochlorothiazide on the pharmacokinetics and pharmacodynamics of febuxostat. METHODS Healthy subjects (36 healthy men and women) received single doses of febuxostat 80 mg alone and febuxostat 80 mg + hydrochlorothiazide 50 mg, separated by 7 days in an open‐label, randomized, crossover fashion. Plasma concentrations of febuxostat and urinary and serum concentrations of uric acid were assessed. RESULTS Mean febuxostat C max , AUC (0–t) , AUC (0–∞) , t 1/2,z , CL/ F and V ss / F values for regimens co‐administration/febuxostat alone were 2.9/2.9 µg ml −1 , 9.3/9.1 µg ml −1 h, 9.6/9.3 µg ml −1 h, 6.5/6.1 h, 8.8/9.3 l h −1 and 45/44 l, respectively. Geometric mean ratios (co‐administration : febuxostat alone) and their 90% confidence intervals for febuxostat plasma C max , AUC (0–t) , and AUC (0–∞) were 1.00 (0.86, 1.17), 1.03 (0.98, 1.09), and 1.04 (0.98, 1.10), respectively; all of the 90% CIs were within the no effect range of 0.8 to 1.25. Serum uric acid C mean,24h , C mean,48h and CL R for both regimens co‐administration/febuxostat alone were 216/203 µmol l −1 , 218/202 µmol l −1 and 9.1/10.1 ml min −1 , respectively. Although serum uric acid C mean,24h and C mean,48h values were higher and CL R values lower after co‐administration compared with dosing of febuxostat alone, with the differences being statistically significant ( P < 0.003), none of the differences (6.5%–9.5%) was considered clinically significant. CONCLUSION Dose adjustment for febuxostat is not necessary when it is administered with hydrochlorothiazide.