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

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 (Cmax) and area under the concentration-time curve from time zero to infinity (AUC0-inf), with coefficient of variation (CV%) for Cmax ranging from 18.1% to 44.9% and for AUC0-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 AUC0-inf representing ~4.2-7.9% of parent exposure. Variability for GD-MET-1 was moderate (Cmax CV%: 30.7%-43.5%; AUC0-inf CV%: 24.8-38.9%). Tigulixostat demonstrated approximately dose-proportional PK, whereas GD-MET-1 showed less consistent proportionality, particularly for Cmax. 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.