P2X3 受体拮抗剂 HRS-2261 在健康受试者中的安全性和药代动力学:一项随机、双盲、安慰剂对照的 1 期研究。

IF 4.6 2区 医学 Q1 PHARMACOLOGY & PHARMACY
Clinical Pharmacokinetics Pub Date : 2024-03-01 Epub Date: 2024-01-10 DOI:10.1007/s40262-023-01330-7
Yuru Fan, Xuan Zhang, Qin Zhang, Liang Zheng, Renpeng Zhou, Cheng Sun, Xihan Wang, Ke Song, Zhusheng He, Honghui Wang, Qian Zhang, Wei Hu
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引用次数: 0

摘要

背景:P2X3受体拮抗剂有望成为难治性或不明原因慢性咳嗽患者的一种治疗选择,这种疾病缺乏已获批准的疗法。本研究评估了新型选择性P2X3受体拮抗剂HRS-2261在健康受试者中的安全性、耐受性和药代动力学(PK):HRS-2261的随机、双盲、安慰剂对照1期试验包括三个阶段:单次升剂量(SAD)研究阶段、食物效应研究阶段和多次升剂量(MAD)研究阶段。在 SAD 阶段,健康受试者被随机分配接受单次口服剂量 HRS-2261(25、100、200、400、800 和 1200 毫克)或安慰剂。SAD 阶段 200 毫克组的受试者在接受安全性评估后直接进入食物效应阶段。在MAD阶段,健康受试者随机接受HRS-2261(50、200和400毫克)或安慰剂治疗,每天两次,连续14天。主要终点是安全性和耐受性:共有 62 和 30 名受试者分别进入了 SAD 和 MAD 阶段,其中 12 名受试者从 SAD 阶段过渡到了食物效应阶段。不良反应(AEs)的发生率和严重程度与剂量无关,除了400毫克组的1例中度不良反应(附睾炎,与治疗无关)外,大多数不良反应都很轻微。9名受试者出现了呕吐症状,其中2名来自SAD阶段,1名来自食物效应阶段,6名来自MAD阶段。SAD 组第 14 天的中位 Tmax 和几何平均 t1/2 分别为 0.9-2.0 小时和 4.1-8.5 小时,MAD 组为 2.0-2.7 小时和 4.6-5.0 小时。SAD 和 MAD 阶段的药物暴露量均小于剂量比例。每天两次重复给药的药物蓄积量较小。食物效应研究结果表明,食物摄入不会影响HRS-2261的血浆暴露量:结论:HRS-2261具有良好的耐受性,口腔不适发生率较低。PK曲线良好。这项研究支持进一步开发HRS-2261,将其作为治疗慢性咳嗽的潜在P2X3受体拮抗剂:试验注册号:Clinical trials.gov,标识符:NCT05274516:试验注册号:Clinical trials.gov,标识符:NCT05274516。试验注册日期:2022 年 3 月 10 日。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Safety and Pharmacokinetics of HRS-2261, a P2X3 Receptor Antagonist, in Healthy Subjects: A Randomized, Double-Blind, Placebo-Controlled Phase 1 Study.

Safety and Pharmacokinetics of HRS-2261, a P2X3 Receptor Antagonist, in Healthy Subjects: A Randomized, Double-Blind, Placebo-Controlled Phase 1 Study.

Background: P2X3 receptor antagonists hold promising potential as a therapeutic option for patients with refractory or unexplained chronic cough, a condition lacking approved therapies. This study assessed the safety, tolerability, and pharmacokinetics (PK) of HRS-2261, a novel selective P2X3 receptor antagonist, in healthy subjects.

Methods: This randomized, double-blinded, placebo-controlled phase 1 trial of HRS-2261 consisted of three phases: the single ascending dose (SAD) study phase, the food-effect study phase, and the multiple ascending dose (MAD) study phase. In the SAD phase, healthy subjects were randomly assigned to receive a single oral dose of HRS-2261 (25, 100, 200, 400, 800, and 1200 mg) or placebo. Subjects in the 200 mg group of the SAD phase progressed directly to the food-effect phase following safety evaluation. In the MAD phase, healthy subjects were randomized to receive HRS-2261 (50, 200, and 400 mg) or placebo twice daily for 14 consecutive days. The primary endpoints were safety and tolerability.

Results: A total of 62 and 30 subjects were enrolled in the SAD and MAD phases, respectively, with 12 subjects from the SAD phase transitioning to the food-effect phase. The incidence and severity of adverse events (AEs) were not dose dependent, and most AEs were mild except for one moderate AE (epididymitis, which was not related to treatment) in the 400 mg group. Dysgeusia was reported in nine subjects, including two from the SAD phase, one from the food-effect phase, and six from the MAD phase. The median Tmax and geometric mean t1/2 were 0.9-2.0 h and 4.1-8.5 h in the SAD, and 2.0-2.7 h and 4.6-5.0 h on day 14 in the MAD, respectively. Drug exposures in the SAD and MAD phases were both less than dose proportional. The accumulation of the drug was slight with repeated twice-daily dosing. Food-effect study results showed that food intake did not affect the plasma exposure of HRS-2261.

Conclusions: HRS-2261 demonstrated good tolerability, with a low incidence of dysgeusia. The PK profile was favorable. This study supports further development of HRS-2261 as a potential P2X3 receptor antagonist for chronic cough.

Trial registration number: Clinical trials.gov, identifier: NCT05274516. Trial registration date: March 10, 2022.

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来源期刊
CiteScore
8.80
自引率
4.40%
发文量
86
审稿时长
6-12 weeks
期刊介绍: Clinical Pharmacokinetics promotes the continuing development of clinical pharmacokinetics and pharmacodynamics for the improvement of drug therapy, and for furthering postgraduate education in clinical pharmacology and therapeutics. Pharmacokinetics, the study of drug disposition in the body, is an integral part of drug development and rational use. Knowledge and application of pharmacokinetic principles leads to accelerated drug development, cost effective drug use and a reduced frequency of adverse effects and drug interactions.
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