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


CONCLUSIONS
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.


OBJECTIVE
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-infinity)), t(1/2,z), CL/F and V(ss)/F values for regimens co-administration/febuxostat alone were 2.9/2.9 microg ml(-1), 9.3/9.1 microg ml(-1) h, 9.6/9.3 microg 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-infinity)) 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 micromol l(-1), 218/202 micromol 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.


CONCLUSIONS
Dose adjustment for febuxostat is not necessary when it is administered with hydrochlorothiazide.
Grabowski
Brian
B
Takeda Global Research & Development Center, Inc., One Takeda Parkway, Deerfield, IL 60015, USA. brian.grabowski@tgrd.com
Khosravan
Reza
R
Wu
Jing-Tao
JT
Vernillet
Laurent
L
Lademacher
Christopher
C
D000328:Adult; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D000069465:Febuxostat; D005260:Female; D006074:Gout Suppressants / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D006801:Humans; D006852:Hydrochlorothiazide / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D013844:Thiazoles / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D014527:Uric Acid / Q000652:urine*; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors*; D055815:Young Adult
D006074:Gout Suppressants; D013844:Thiazoles; D006852:Hydrochlorothiazide; D000069465:Febuxostat; D014527:Uric Acid; D014969:Xanthine Oxidase