A Phase I Dose-Escalation Study of the Pharmacokinetics, Pharmacodynamics, and Safety of a Single Oral Dose of Tigulixostat

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Aim: Tigulixostat is a promising selective xanthine oxidase inhibitor under clinical development for the treatment of hyperuricemia. The aim of this study was to evaluate the pharmacokinetics (PK), pharmacodynamics (PD), and safety of tigulixostat, along with its primary active metabolite, GD-MET-1, following single oral administration in healthy Chinese subjects. Methods: A single center, open-label, dose-escalation study was conducted in healthy Chinese subjects who received single oral doses of tigulixostat ranging from 25 to 300 mg. Serial blood and urine samples were collected for PK and PD analysis. Safety was monitored throughout the study. Results: Thirty subjects were enrolled, with six subjects per dose group. Tigulixostat exhibited dose-proportional increases in both maximum plasma concentration (C max ) and area under the concentration–time curve from time zero to infinity (AUC 0-inf ), with coefficient of variation (CV%) for C max ranging from 18.1% to 44.9% and for AUC 0-inf from 20.4% to 66.9%. The 24-hour mean serum uric acid decreased by 12.8% to 28.8% from baseline on Day 1, with greater reductions at higher doses. GD-MET-1 exposure increased with dose, with AUC 0-inf representing ~4.2– 7.9% of parent exposure. Variability for GD-MET-1 was moderate (C max CV%: 30.7%– 43.5%; AUC 0-inf CV%: 24.8– 38.9%). Tigulixostat demonstrated approximately dose-proportional PK, whereas GD-MET-1 showed less consistent proportionality, particularly for C max . No serious adverse events occurred, and all treatment-emergent adverse events were mild in severity. Conclusion: These findings demonstrate that tigulixostat exhibits approximately dose-proportional PK, with linear elimination and predictable exposure across the 25– 300 mg range. A dose-dependent reduction in serum uric acid was observed up to 200 mg, with a plateau effect at 300 mg. The PK profile of GD-MET-1 indicated lower systemic exposure and less consistent dose proportionality compared with the parent compound, suggesting a supportive rather than dominant role in PD activity. The favorable safety and tolerability profile reinforces tigulixostat’s potential as a novel therapeutic agent for the management of hyperuricemia. Plain Language Summary: What is already known about this subject Xanthine oxidase inhibitors such as allopurinol and febuxostat are widely used for the treatment of hyperuricemia but may have limitations including hypersensitivity reactions, cardiovascular risk concerns, or limited efficacy in some patients. Tigulixostat is a novel, selective xanthine oxidase inhibitor under clinical development, designed to offer improved safety and efficacy profiles. There is limited data on the pharmacokinetics and pharmacodynamics of tigulixostat in Chinese populations. What this study adds This is the first study to characterize the pharmacokinetics, pharmacodynamics, and safety of tigulixostat in healthy Chinese subjects. The drug demonstrated approximately dose-proportional exposure and a clear dose-dependent urate-lowering effect across a 25-300 mg dose range. The pharmacokinetic profile of GD-MET-1 indicated lower systemic exposure and less consistent dose proportionality compared with the parent compound, suggesting a supportive rather than dominant role in pharmacodynamics activity. Tigulixostat was well tolerated, with only mild adverse events observed.