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-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. CONCLUSION: Dose adjustment for febuxostat is not necessary when it is administered with hydrochlorothiazide.
RCT Entities:
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-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. CONCLUSION: Dose adjustment for febuxostat is not necessary when it is administered with hydrochlorothiazide.
Authors: Michael A Becker; H Ralph Schumacher; Robert L Wortmann; Patricia A MacDonald; Denise Eustace; William A Palo; Janet Streit; Nancy Joseph-Ridge Journal: N Engl J Med Date: 2005-12-08 Impact factor: 91.245
Authors: M A Becker; J Kisicki; R Khosravan; J Wu; D Mulford; B Hunt; P MacDonald; N Joseph-Ridge Journal: Nucleosides Nucleotides Nucleic Acids Date: 2004-10 Impact factor: 1.381
Authors: Reva C Lawrence; David T Felson; Charles G Helmick; Lesley M Arnold; Hyon Choi; Richard A Deyo; Sherine Gabriel; Rosemarie Hirsch; Marc C Hochberg; Gene G Hunder; Joanne M Jordan; Jeffrey N Katz; Hilal Maradit Kremers; Frederick Wolfe Journal: Arthritis Rheum Date: 2008-01
Authors: Bishoy Kamel; Garry G Graham; Sophie L Stocker; Zhixin Liu; Kenneth M Williams; Jane E Carland; Kevin D Pile; Richard O Day Journal: Br J Clin Pharmacol Date: 2020-06-18 Impact factor: 4.335