Pharmacokinetics and pharmacodynamics of febuxostat, a new non-purine selective inhibitor of xanthine oxidase in subjects with renal impairment

Am J Ther. 2005 Jan-Feb;12(1):22-34. doi: 10.1097/00045391-200501000-00005.

Abstract

To assess the safety, pharmacokinetics, and pharmacodynamics of febuxostat in subjects with normal renal function or renal impairment, febuxostat (80 mg/d) was orally administered for 7 days to subjects with normal renal function (n = 11, CLcr >80 mL/min/1.73 m) or to subjects with mild (n = 6, CLcr 50-80 mL/min/1.73 m), moderate (n = 7, CLcr 30-49 mL/min/1.73 m), or severe renal impairment (n = 7, CLcr 10-29 mL/min/1.73 m). The pharmacokinetics of febuxostat and its active quantifiable metabolites 67M-1, 67M-2, and 67M-4 as well as the pharmacodynamics of uric acid, xanthine, and hypoxanthine were determined in plasma (or serum) and urine. Febuxostat was safe and well tolerated. Regression analyses indicated that febuxostat tmax and Cmax,u values were not affected by CLcr. However, for AUC24,u, CLu/F, and t1/2z, regression analyses indicated a statistically significant relationship with CLcr. With the exception of 67M-1 Cmax, regression analyses for 67M-2 and 67M-4 Cmax, and for AUC24 for all 3 metabolites indicated a statistically significant linear relationship with CLcr. Irrespective of renal function group, the mean serum uric acid concentrations decreased by 55% to 64% by day 7. Although plasma exposure to febuxostat and its metabolites was generally higher in subjects with increasing degrees of renal impairment, the percentages of decrease in serum uric acid were comparable regardless of the renal function group. A once-daily 80-mg dose of febuxostat appears to be safe and well tolerated in different renal function groups and does not appear to require any dose adjustment based on differences in renal function.

Publication types

  • Clinical Trial
  • Multicenter Study

MeSH terms

  • Adult
  • Aged
  • Area Under Curve
  • Blood Proteins / metabolism
  • Febuxostat
  • Female
  • Half-Life
  • Humans
  • Male
  • Middle Aged
  • Regression Analysis
  • Renal Insufficiency / blood
  • Renal Insufficiency / classification
  • Renal Insufficiency / metabolism*
  • Severity of Illness Index
  • Thiazoles / metabolism
  • Thiazoles / pharmacokinetics*
  • Thiazoles / pharmacology
  • Uric Acid / blood
  • Xanthine Oxidase / antagonists & inhibitors*

Substances

  • Blood Proteins
  • Thiazoles
  • Febuxostat
  • Uric Acid
  • Xanthine Oxidase