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Effect of food or antacid on febuxostat pharmacokinetics and pharmacodynamics in healthy subjects

2005; Wiley; Volume: 77; Issue: 2 Linguagem: Inglês

10.1016/j.clpt.2004.12.083

1532-6535

Reza Khosravan, Brian Grabowski, J WU, Nancy Joseph‐Ridge, Laurent Vernillet,

Biochemical and Molecular Research

Febuxostat is a novel non-purine selective inhibitor of xanthine oxidase (NP-SIXO) being developed for the management of hyperuricemia in patients with gout. Aim The effects of food and antacid on oral febuxostat pharmacokinetics (PK) and pharmacodynamics (PD) were evaluated. Methods In 4 phase-1, two-period, crossover studies, male and female subjects received either a single dose (SD) of 40 mg (n=23) or 120 mg (n=19), or multiple dose (MD) 80 mg daily for 6 days (n=23) of febuxostat under non-fasting[test (T)] and fasting[reference (R)] conditions; or received a single 80 mg dose with (T) and without (R) an antacid (800 mg Mg(OH)2-900 mg Al(OH)3). Plasma febuxostat (LC-MS/MS method) and serum uric acid (sUA, PD marker, enzymatic assay) concentrations were assessed. Results A delay of tmax was observed with both food and antacid. Point estimates (PE) and confidence intervals (CI) for T and R ratios/differences are shown below for febuxostat Cmax, AUC and sUA 24-hour mean concentration (Cmean,24). (see Table) Even though food caused a decrease in the absorption rate and extent of febuxostat in all food effect studies, this decrease was not associated with a decrease in febuxostat PD effect (sUA), when evaluated in the 80 mg MD study. Despite a decrease in the absorption rate of febuxostat, antacid had no effect on the extent of febuxostat absorption. Febuxostat was safe and well tolerated in all studies. Conclusion Febuxostat can be administered regardless of food or antacid intake. Clinical Pharmacology & Therapeutics (2005) 77, P50–P50; doi: 10.1016/j.clpt.2004.12.083 Febuxostat Dose Febuxostat Cmax Febuxostat AUC1 Cmean,24 (%) Food Effect 40 mg SD 0.54 (0.48–0.61)2 0.81 (0.77–0.85)2 - 80 mg MD 0.51 (0.44–0.60)2 0.82 (0.78–0.87)2 6 (4–10) 120 mg SD 0.62 (0.52–0.74)2 0.84 (0.79–0.90)2 - Antacid Effect 80 mg SD 0.68 (0.58–0.79)2 0.85 (0.81–0.90)2 - 1 AUC∞[single dose (SD)] or AUC24[multiple dose (MD)] 2 T/R ratio PE (90% CI, log-transformed data) for febuxostat PK parameter ratios T-R difference PE (95% CI) for the % change from the baseline in Cmean,24