Effect of hydrochlorothiazide on the pharmacokinetics and pharmacodynamics of febuxostat, a non-purine selective inhibitor of xanthine oxidase

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.