Effects of age and gender on febuxostat pharmacokinetics, pharmacodynamics, and safety in healthy subjects

Abstract

Background 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 age and gender on the pharmacokinetics (PK), pharmacodynamics (PD), and safety of febuxostat were evaluated. Methods In a phase‐1, parallel group, open‐label, multiple dose study, male (M) and female (F) subjects between 19–40 years old[young (Y), 12M/12F] and 65–76 years old[elderly (E), 12M/12F] received once daily 80 mg oral doses of febuxostat for 7 days. Blood samples were collected to assess the PK of febuxostat and its active metabolites (67M‐1, 67M‐2, 67M‐4) as well as its effect on uric acid (PD marker). Protein binding and safety of febuxostat were also assessed. Results The results are shown in the table below. The overall incidence of study drug related adverse events (AEs) was lower in M than in F (13% vs 54%) and in Y than in E (25% vs 42%). The most common AEs were headache and constipation. The majority of AEs were mild in severity. Conclusion Neither age nor gender had any clinically significant effect on the PK, PD, and safety of febuxostat. Therefore, febuxostat does not require any dose adjustment based on age or gender. Clinical Pharmacology & Therapeutics (2005) 77, P50–P50; doi: Mean± SD Plasma Pharmacokinetic and Serum Uric Acid (sUA) Parameters on Day 7 Age Gender Analyte Parameter Y E M F FebuxostatCmax,u (ng/mL)28±1227±924±1031±101,2AUC24,u (ng·h/mL)56±1961±2054±2363±151,2fu (%)0.7±0.10.7±0.20.7±0.10.7±0.167M‐1AUC24 (ng·h/mL)225±63265±84224±68265±8067M‐2AUC24 (ng·h/mL)229±76243±69240±81232±6367M‐4AUC24 (ng·h/mL)235±77270±125223±70281±125sUACmean,24 (%change)−55±8−56±9−52±7−59±81 Cmax,u or AUC24,u: Unbound Cmax or AUC24; fu: Unbound fraction; Cmean,24: sUA 24‐hour mean concentration;1 Statistically significantly different from M (p≤ 0.05)2 Not statistically significantly different from M (p>0.05) with weight as a covariate

The Effect of Mild and Moderate Hepatic Impairment on Pharmacokinetics, Pharmacodynamics, and Safety of Febuxostat, a Novel Nonpurine Selective Inhibitor of Xanthine Oxidase

“…In fact, the results from other phase I studies in which normal healthy subjects received the same dosing regimen showed percentage decreases in serum uric acid of 58.2% ± 11.1%, 54.9% ± 7.5%, and 51.2% ± 14.3%. 26,29,30 These mean values were slightly lower than those observed in the normal hepatic group (ie, 62.5 ± 7.5%) and closer to those observed in the mild and moderate hepatic function groups (ie, 48.9 ± 13.5% and 47.8 ± 6.8%, respectively). Therefore, from a clinical standpoint, the lower percentage decreases in serum uric acid in subjects with hepatic impairment does not require any dose adjustments.…”

“…At the end, despite statistically significant differences between the mean percentage decrease in serum uric acid C mean,24 in subjects with hepatic impairment as compared to that in subjects with normal hepatic function, these differences were relatively small (13% to 14%) and were not considered clinically significant. In fact, the results from other phase I studies in which normal healthy subjects received the same dosing regimen showed percentage decreases in serum uric acid of 58.2% ± 11.1%, 54.9% ± 7.5%, and 51.2% ± 14.3% 26 , 29 , 30 . These mean values were slightly lower than those observed in the normal hepatic group (ie, 62.5 ± 7.5%) and closer to those observed in the mild and moderate hepatic function groups (ie, 48.9 ± 13.5% and 47.8 ± 6.8%, respectively).…”

Febuxostat

“…Age, race, and gender do not affect the pharmacokinetics or pharmacodynamics of febuxostat. 1,10,13 Concentrations of febuxostat and its metabolites were increased slightly in patients with impaired renal function; however, reductions in serum uric acid were similar regardless of the level of renal function impairment. It does not appear that dosage adjustments are necessary in patients with mild to severe renal impairment.…”

Febuxostat: A Novel, Non-Purine Xanthine Oxidase Inhibitor

“…26,28 Age and gender did not appear to significantly affect the pharmacokinetics, pharmacodynamics, or safety of febuxostat. 31 Febuxostat elimination occurs primarily by the liver via conjugation and oxidative metabolism. hepatic impairment (Child-Pugh Class A and B impairment, respectively) did not appear to affect febuxostat clearance.…”