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已发表论文
一项关于单次口服替古列司他剂量的 I 期剂量递增研究：药代动力学、药效学及安全性
Authors Tao J, Liu S, Liu R, Xue W , Sun S, Wang S, Sun C, Li Y, Wang C, Tian X
Received 29 April 2025
Accepted for publication 3 December 2025
Published 12 December 2025 Volume 2025:19 Pages 11007—11020
DOI https://doi.org/10.2147/DDDT.S537604
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 3
Editor who approved publication: Dr Leonidas Panos
Jun Tao,1,2,* Shuaibing Liu,1,2,* Ruijuan Liu,1,2 Wenhua Xue,1,2 Suke Sun,1 Suyun Wang,1 Chunjie Sun,1 Yidong Li,1 Chengzeng Wang,3 Xin Tian1,2
1Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China; 2Henan Key Laboratory of Precision Clinical Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China; 3Henan Institute of Interconnected Intelligent Health Management, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China
*These authors contributed equally to this work
Correspondence: Xin Tian, Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China, Tel +86-371-6629-5652, Email tianx@zzu.edu.cn
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.
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.
Keywords: tigulixostat, GD-MET-1, xanthine oxidase inhibitor, hyperuricemia, dose escalation, pharmacokinetics, pharmacodynamics, safety
1Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China; 2Henan Key Laboratory of Precision Clinical Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China; 3Henan Institute of Interconnected Intelligent Health Management, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China
*These authors contributed equally to this work
Correspondence: Xin Tian, Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China, Tel +86-371-6629-5652, Email tianx@zzu.edu.cn
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.
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.
Keywords: tigulixostat, GD-MET-1, xanthine oxidase inhibitor, hyperuricemia, dose escalation, pharmacokinetics, pharmacodynamics, safety