An Open-Label, Single and Multiple Dose Study to Evaluate the Pharmacokinetics and Safety of Fezolinetant in Healthy Chinese Female Subjects.

IF 4.7 2区医学 Q1 CHEMISTRY, MEDICINAL

Drug Design, Development and Therapy Pub Date : 2025-03-26 eCollection Date: 2025-01-01 DOI:10.2147/DDDT.S486562

Yang Li, Yue Liu, Megumi Iwai, Masato Takeuchi, Nan Song, Yuan Li, Aixin Shi

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引用次数: 0

Abstract

Purpose: To evaluate pharmacokinetics (PK) and safety of fezolinetant after single-dose and multiple-dose administration of 15, 30, and 60 mg in healthy Chinese women.

Patients and methods: This was a fixed-sequence crossover study in 16 healthy Chinese female subjects, 18-45 years old. All received single doses of fezolinetant 15 mg, 30 mg or 60 mg with a 3-day washout. From Day 10, subjects received multiple doses of 30 mg fezolinetant once-daily for 7 days. PK parameters were obtained during the single- and multiple-dose periods. Safety assessments were based on adverse events, vital signs, and laboratory tests.

Results: Fezolinetant exhibited rapid absorption, with median time of the maximum concentration (t_max) 1.50 to 1.75 hours after single-dose administration of fezolinetant tablets in the fasted state, followed by a decline in plasma levels, with a mean t_1/2 of 6.12-7.69 hours at dose levels of 15, 30 and 60 mg. There was a dose-proportional increase in maximum concentration and total exposure for fezolinetant across the doses studied. Mean peak concentration (C_max) values were 221, 439 and 834 ng/mL, for the 15, 30, and 60 mg doses, respectively. The drug exposure parameters had a low-to-moderate variability (21.1-39.7%). Minimum accumulation was observed after multiple doses. Metabolite ES259564 showed rapid formation following a single dose of fezolinetant, with a median t_max of 1.50-2.00 hours. Plasma levels then declined, with mean t_1/2 ranging from 5.72-6.31 hours. Dose-proportional increases in C_max and AUC_inf were observed following single-doses of fezolinetant. Steady state was achieved on the second day after starting multiple-dose administration. In total, 3 (18.8%) subjects experienced 4 drug-related treatment-emergent adverse events; all mild in severity.

Conclusion: Linear PK was confirmed within the dose range of 15 to 60 mg in healthy Chinese women.

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非唑啉坦在中国健康女性体内的药代动力学和安全性的开放标签、单剂量和多剂量研究。

目的：评价非唑啉坦在中国健康女性15、30和60 mg单次和多次给药后的药代动力学（PK）和安全性。患者和方法：这是一项固定序列交叉研究，16名18-45岁的健康中国女性受试者。所有患者均接受单剂量fezolinetant 15mg、30mg或60mg， 3天洗脱期。从第10天开始，受试者接受多剂量30mg非唑啉坦，每天一次，连续7天。获得单次和多次给药期间的PK参数。安全性评估基于不良事件、生命体征和实验室测试。结果：非唑啉内坦具有快速吸收的特点，在空腹状态下单次给药后最大浓度（tmax）中位时间为1.50 ~ 1.75 h，随后血浆浓度下降，在15、30、60 mg剂量下，平均t1/2为6.12 ~ 7.69 h。在研究的各个剂量中，fezolinetant的最大浓度和总暴露量呈剂量正比增加。15、30和60 mg剂量的平均峰值浓度（Cmax）分别为221、439和834 ng/mL。药物暴露参数具有中低变异性（21.1-39.7%）。多次给药后观察到最小累积。代谢物ES259564在单剂量fezolinetant后快速形成，中位tmax为1.50-2.00小时。血浆水平随后下降，平均t1/2在5.72-6.31小时之间。单次给药后Cmax和aucf呈剂量比例增加。多剂量给药后第2天达到稳定状态。共有3名（18.8%）受试者经历了4次药物相关治疗不良事件；都是轻微的。结论：在15 ~ 60mg的剂量范围内，中国健康女性PK呈线性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Drug Design, Development and Therapy CHEMISTRY, MEDICINAL-PHARMACOLOGY & PHARMACY

CiteScore

9.00

自引率

0.00%

发文量

382

审稿时长

>12 weeks

期刊介绍： Drug Design, Development and Therapy is an international, peer-reviewed, open access journal that spans the spectrum of drug design, discovery and development through to clinical applications. The journal is characterized by the rapid reporting of high-quality original research, reviews, expert opinions, commentary and clinical studies in all therapeutic areas. Specific topics covered by the journal include: Drug target identification and validation Phenotypic screening and target deconvolution Biochemical analyses of drug targets and their pathways New methods or relevant applications in molecular/drug design and computer-aided drug discovery* Design, synthesis, and biological evaluation of novel biologically active compounds (including diagnostics or chemical probes) Structural or molecular biological studies elucidating molecular recognition processes Fragment-based drug discovery Pharmaceutical/red biotechnology Isolation, structural characterization, (bio)synthesis, bioengineering and pharmacological evaluation of natural products** Distribution, pharmacokinetics and metabolic transformations of drugs or biologically active compounds in drug development Drug delivery and formulation (design and characterization of dosage forms, release mechanisms and in vivo testing) Preclinical development studies Translational animal models Mechanisms of action and signalling pathways Toxicology Gene therapy, cell therapy and immunotherapy Personalized medicine and pharmacogenomics Clinical drug evaluation Patient safety and sustained use of medicines.