Population pharmacokinetic analysis of febuxostat with high focus on absorption kinetics and food effect.

ABSTRACT

Febuxostat is commonly used in clinic for the treatment of hyperuricemia. Multiple-peak phenomenon has been observed in human plasma concentration-time profiles of febuxostat, but has not been paid enough attention in previous research. This study takes a pivotal step forward by conducting a comprehensive population pharmacokinetic (PopPK) analysis of febuxostat in a healthy Chinese cohort, with a central focus on delineating its absorption profile under contrasting fasting and fed conditions, while concurrently assessing the influence of food alongside other potential covariates on febuxostat's PK profile. The plasma concentration data used for modeling was obtained from two bioequivalence (BE) studies. Subjects were administered febuxostat 20 mg or 80 mg under fasting or fed condition. Goodness-of-fit plots, visual predict check (VPC), and normalized prediction distribution error (NPDE) were used for model evaluation. Based on the established model, PK profiles in healthy Caucasian subjects were simulated with parameter adjustment for race difference on clearance and bioavailability. Data from 128 subjects were used in the PopPK analysis. Febuxostat concentration-time curves were described by a two-compartment model with two deposit absorption compartments and lag times (Tlag). Prandial states (Food) showed significant impact on absorption rate ka1 and ka2, as well as Tlag1, and body weight was identified as a significant covariate on the apparent distribution volume. The PopPK analysis of febuxostat in healthy Chinese volunteers, under both fasted and fed conditions, successfully characterized its PK profile and underscored the significant influence of food on absorption. The potential difference of absorption between Chinese population and Caucasian population indicated from the simulations needs further investigation.