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

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

10.1016/j.clpt.2004.12.084

1532-6535

Reza Khosravan, Michael Kukulka, J WU, Nancy Joseph‐Ridge, Laurent Vernillet,

Hepatitis C virus research

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: 10.1016/j.clpt.2004.12.084 Table 1. Mean± SD Plasma Pharmacokinetic and Serum Uric Acid (sUA) Parameters on Day 7 Age Gender Analyte Parameter Y E M F Febuxostat Cmax,u (ng/mL) 28±12 27±9 24±10 31±101,2 AUC24,u (ng·h/mL) 56±19 61±20 54±23 63±151,2 fu (%) 0.7±0.1 0.7±0.2 0.7±0.1 0.7±0.1 67M-1 AUC24 (ng·h/mL) 225±63 265±84 224±68 265±80 67M-2 AUC24 (ng·h/mL) 229±76 243±69 240±81 232±63 67M-4 AUC24 (ng·h/mL) 235±77 270±125 223±70 281±125 sUA Cmean,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