Tianqi Zhong, Kaizong Huang, LuYao Han, Wenbo Pang, Yan Xia, Shengjun Qu, Guo Yu, Yangsheng Chen, Hongwei Fan
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引用次数: 0
Abstract
Objective: This Phase I clinical trial aimed to address the knowledge gap regarding topiroxostat's use outside Japan by characterizing its pharmacokinetic profile, safety, and efficacy in healthy Chinese subjects.
Methods: The trial followed a randomized, open-label, three-dose group design, enrolling 12 healthy participants and administering topiroxostat at three different dose levels. The study utilized NONMEM software for pharmacokinetic analysis, evaluating the impact of demographic and biochemical covariates on drug disposition.
Results: Pharmacokinetic analysis shows the peak drug concentration (Cmax) under a single oral administration of 20, 40, and 80 mg of Topiroxostat, which was found in healthy subjects to be 215.46 ± 94.04 ng/mL, 473.74 ± 319.83 ng/mL and 1009.63 ± 585.98 ng/mL, respectively. The time to peak drug concentration (Tmax) was longer in females (0.79-0.98 h) than in males (0.53-0.93 h). Activated partial thromboplastin time (APTT) and triglycerides (TG) were included as covariates for the typical value of the absorption rate constant (TVKA) in our pharmacokinetic model. The dose (DOSE) was considered a covariate for the typical value of bioavailability (TVF1), and sex (SEX) was considered a covariate for the typical value of clearance (TVCL). The typical population values for topiroxostat included Q/F at 4.91 L/h, KA at 0.657 h-¹, Vc/F at 32.5 L, Vp/F at 30 L, and CL/F at 124 L/h.
Conclusion: The trial successfully established the pharmacokinetic parameters of topiroxostat in a Chinese population, confirming its safety and efficacy. The results support the need for individualized dosing strategies and optimize therapeutic outcomes.
期刊介绍：
Current Drug Metabolism aims to cover all the latest and outstanding developments in drug metabolism, pharmacokinetics, and drug disposition. The journal serves as an international forum for the publication of full-length/mini review, research articles and guest edited issues in drug metabolism. Current Drug Metabolism is an essential journal for academic, clinical, government and pharmaceutical scientists who wish to be kept informed and up-to-date with the most important developments. The journal covers the following general topic areas: pharmaceutics, pharmacokinetics, toxicology, and most importantly drug metabolism.
More specifically, in vitro and in vivo drug metabolism of phase I and phase II enzymes or metabolic pathways; drug-drug interactions and enzyme kinetics; pharmacokinetics, pharmacokinetic-pharmacodynamic modeling, and toxicokinetics; interspecies differences in metabolism or pharmacokinetics, species scaling and extrapolations; drug transporters; target organ toxicity and interindividual variability in drug exposure-response; extrahepatic metabolism; bioactivation, reactive metabolites, and developments for the identification of drug metabolites. Preclinical and clinical reviews describing the drug metabolism and pharmacokinetics of marketed drugs or drug classes.
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