A Phase I, Randomized, Single-Ascending-Dose, Multiple-Dose, and Food-Effect Trial of the Safety, Efficacy, and Pharmacokinetics of Topiroxostat in Healthy Chinese Participants

Abstract

Abstract Background: As the structure of the human diet changes, the prevalence of hyperuricemia is increasing each year. Hyperuricemia and its comorbidities, such as gout, severely affect quality of life. Moreover, hyperuricemia causes renal impairment and is associated with chronic kidney disease. Topiroxostat, a selective xanthine oxidoreductase inhibitor, has been approved to treat hyperuricemia or gout in Japan. Topiroxostat has shown good tolerance and efficacy in the Japanese population. However, its pharmacokinetic (PK) characteristics, efficacy, and safety in the Chinese population remains unknown.Objective: This trial evaluated the PK profile, safety, efficacy, and food effects of Topiroxostat in healthy Chinese participants.Methods: The major endpoint was determination of the PK profile of Topiroxostat. Topiroxostat concentrations were detected with LC-MS/MS. PK parameters were calculated in Phoenix WinNonlin 8.1. Minor endpoints were safety and efficacy assessments. Assessment of adverse events and safety was performed by clinicians. Plasma uric acid concentration (ΔECmax and ΔAUEC) was determined as the pharmacodynamic index. This study consisted of three arms: single ascending dose (20, 40, and 80 mg, N = 10), multiple dose (80 mg BID, 7 days, N = 10), and food effects (40 mg single dose, fasting-fed cross-over design, N = 10).Results: In the single-ascending-dose arm, Topiroxostat showed rapid absorption and excretion, with Tmax <1.6 h and T1/2 2.49‐3.72 h. Additionally, Topiroxostat showed a wide distribution, on the basis of moderate Vz/F (242.8‐336.36 L). The main PK parameters Cmax, AUC0-t, and AUC0-C showed a linear relationship with dose (R2 = 0.5146, 0.8416, 0.8386, respectively). In the multiple-dose arm, no significant differences were observed in Cmin on days 3‐6 (P = 0.265). No serious adverse events were observed. Regarding efficacy, plasma uric acid levels were controlled to low levels during multiple-dose administration. In the food-effects arm, the fed group showed a lower Cmax than the fasting group (316.00 ± 135.81 vs. 478.40 ± 175.42 ng/mL, P = 0.033) but demonstrated better efficacy (ΔECmax, P < 0.001; ΔAUEC, P < 0.001).Conclusions: Topiroxostat showed rapid absorption and a broad distribution in healthy Chinese adults. Additionally, it showed good safety and tolerance in the Chinese population. Moreover, the pharmacodynamic profile indicated that post cibum administration increased the efficacy of Topiroxostat.