背景:P2X3受体拮抗剂作为难治性或原因不明的慢性咳嗽患者的治疗选择具有良好的潜力,缺乏批准的治疗方法。这项研究评估了安全性,耐受性,和药代动力学(PK)的HRS-2261,一种新型的选择性P2X3受体拮抗剂,在健康的科目。
方法:这是随机的,双盲,HRS-2261的安慰剂对照1期试验包括三个阶段:单次递增剂量(SAD)研究阶段,食物效应研究阶段,和多次递增剂量(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HRS-2261(25,100,200,400,800和1200mg)或安慰剂.SAD阶段的200mg组中的受试者在安全性评估后直接进展到食物效应阶段。在MAD阶段,健康受试者随机接受HRS-2261(50,200和400mg)或安慰剂,每日2次,连续14天.主要终点是安全性和耐受性。
结果:共有62和30名受试者参加了SAD和MAD阶段,分别,有12名受试者从SAD阶段过渡到食物效应阶段。不良事件(AE)的发生率和严重程度不是剂量依赖性的,除1例中度不良事件(附睾炎,这与400mg组的治疗无关)。据报道,九名受试者出现了味觉障碍,包括两个来自SAD阶段,一个来自食物效应阶段,和六个来自MAD阶段。SAD的Tmax中位数和几何平均值t1/2分别为0.9-2.0h和4.1-8.5h,MAD第14天的2.0-2.7小时和4.6-5.0小时,分别。SAD和MAD阶段的药物暴露均小于剂量比例。每天重复两次给药,药物的积累很少。食物效应研究结果表明,食物摄入不影响HRS-2261的血浆暴露。
结论:HRS-2261表现出良好的耐受性,味觉障碍的发病率很低。PK曲线是有利的。这项研究支持进一步开发HRS-2261作为慢性咳嗽的潜在P2X3受体拮抗剂。
背景:临床试验,标识符:NCT05274516。试用注册日期:2022年3月10日。
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.
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.
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.
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.
Clinical trials.gov, identifier: NCT05274516.
Trial registration date: March 10, 2022.