This study examined the effect of co-administration of febuxostat, an investigational urate lowering therapy, and hydrochlorothiazide on the pharmacokinetics and pharmacodynamics of febuxostat.
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.
Mean febuxostat Cmax, AUC(0–t), AUC(0–∞), t1/2,z, CL/F and Vss/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 Cmax, 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 Cmean,24h, Cmean,48h and CLR 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 Cmean,24h and Cmean,48h values were higher and CLR 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.
Dose adjustment for febuxostat is not necessary when it is administered with hydrochlorothiazide.