Higher Febuxostat Exposure Observed in Asian Compared with Caucasian Subjects Independent of Bodyweight

Background and Objective Febuxostat is a xanthine oxidase inhibitor indicated for gout and hyperuricemia. This work investigates potential clinically relevant covariates for febuxostat pharmacokinetics with a special focus on Asian race and bodyweight. Methods Febuxostat plasma concentrations from 141 male subjects were obtained from two phase II studies in patients with hyperuricemia/gout (NCT02246673, NCT02317861) and one study in healthy volunteers (NCT01883167). Subjects were administered febuxostat oral doses from 10 to 80 mg. The pharmacokinetics of febuxostat was analyzed using non-linear mixed-effects modeling as implemented in NONMEM 7.3.0. The dataset consisted of racially diverse subjects, 40% being Japanese, 10% of unknown Asian origin, 39% Caucasian, and 10% Black. Most subjects (n = 92, 63%) had normal creatinine clearance (90 mL/min), while 52 subjects (36%) had mild renal impairment (creatinine clearance > 60 to < 90) at baseline. The effect of disease state, body weight, and creatinine clearance on febuxostat pharmacokinetics was investigated using stepwise covariate modeling. Results Febuxostat pharmacokinetics was well described by a two-compartment disposition model. Asian race was the only covariate resulting in a potentially clinically important increase in febuxostat area under the curve (1.64-fold, 90% confidence interval 1.48-1.79) compared with Caucasian individuals. The difference in body weight between Asian and Caucasian subjects did not explain the difference in febuxostat exposure. Absorption was modeled as a sequential zero- to first-order process with lag-time. Conclusions In this pooled analysis of three studies, we show that Asian individuals have a 1.64-fold higher febuxostat exposure than Caucasians, independent of bodyweight or other investigated covariates. These findings may be of importance when selecting starting febuxostat doses in Asian patients.

Automated summary

This study investigated the potential covariates for febuxostat pharmacokinetics, with a special focus on Asian race and bodyweight. The results showed that Asians have a 1.64-fold higher febuxostat exposure compared to Caucasians, independent of bodyweight or other investigated covariates. These findings may be important for selecting starting febuxostat doses in Asian patients.