Pharmacokinetics and tolerability of febuxostat after oral administration in healthy Chinese volunteers: a randomized, open-label, single- and multiple-dose three-way crossover study

Objective: Febuxostat is a novel non-purine selective inhibitor of xanthine oxidase indicated for the chronic management of hyperuricemia in patients with gout. The aim of the present study was to evaluate the pharmacokinetic properties and tolerability of single and multiple oral administrations of febuxostat capsules in healthy Chinese volunteers. Methods: This open label, single- and multiple-dose three-way crossover study was conducted in healthy Chinese volunteers. Subjects were randomized to receive a single dose of febuxostat 40, 80, or 120 mg in separate trial periods, with a 1-week washout between periods. Those allocated to the 40 mg and 80 mg dose continued into the multiple-dose phase, in which they received 40 mg or 80 mg once daily for 6 consecutive days. During the course of the study, blood samples were collected and the concentrations of febuxostat were determined using LC-MS/MS. Pharmacokinetic parameters were estimated using a noncompartmental model. Tolerability was determined using clinical evaluation and monitoring of adverse events (AEs). Results: 12 healthy Chinese volunteers were enrolled and completed 3 treatment periods. After oral administration of single doses of 40, 80, and 120 mg of febuxostat, the mean (SD) C-max was 2,835.43 (1,136.41), 5,356.75 (1,711.33), and 7,718.21 (2,446.34) ng/mL, respectively; the AUC(0-48h) was 8,821.10 (3,018.35), 17,854.46 (5,113.28), and 30,832.05 (10,992.20) ngxh/ mL; the AUC(0-infinity) was 8,990.33 (3,046.14), 18,193.58 (5,160.80), and 31,466.93 (1,1074.74) ngxh/ mL; the t(1/2) was 5.95 (2.71), 9.41 (7.47), and 12.34 (10.34) hours; the Cl/F was 4.81 (1.18), 4.70 (1.21), and 4.18(1.19) L/h; and the Vz/F was 39.66 (16.69), 62.72 (51.41), and 73.41 (64.84) L. After administration of multiple doses of 40 and 80 mg febuxostat, the mean (SD) C-max,C-ss was 2,762.38 (1,331.96) and 5,047.27 (1,456.57) ng/mL; the C-min,C-ss was 124.10 (6.32) and 46.93 (15.86) ng/mL; the AUC(ss,0-tau) was 8,525.49 (2,160.64) and 16,757.12 (4,223.17) ngxh /mL; the steady-state plasma concentration (C-ss) was 355.23 (90.03) and 698.21 (175.97) ng/mL; the t(1/2) was 7.68 (3.30) and 11.33 (6.94) hours; the Cl/F was 4.99 (1.30) and 5.05 (1.22) L/h; and the Vz/F was 54.10 (24.10) and 85.51 (65.99) L. No serious AEs were reported, and there were no discontinuations due to AEs. Conclusion: The PK of febuxostat exhibited dose proportional kinetics from 40 to 120 mg dose. After multiple doses, the pharmacokinetic parameters of febuxostat were consistent with those after single doses. There was no accumulation in febuxostat exposure in healthy Chinese between multiple doses and single dose. At the doses studied, febuxostat appeared to be well tolerated in these healthy volunteers.