PMID- 38198010 OWN - NLM STAT- MEDLINE DCOM- 20240321 LR - 20240416 IS - 1179-1926 (Electronic) IS - 0312-5963 (Linking) VI - 63 IP - 3 DP - 2024 Mar TI - Safety and Pharmacokinetics of HRS-2261, a P2X3 Receptor Antagonist, in Healthy Subjects: A Randomized, Double-Blind, Placebo-Controlled Phase 1 Study. PG - 293-302 LID - 10.1007/s40262-023-01330-7 [doi] AB - 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 T(max) and geometric mean t(1/2) 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. CI - (c) 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG. FAU - Fan, Yuru AU - Fan Y AD - Department of Clinical Pharmacology, The Second Affiliated Hospital of Anhui Medical University, No. 678 Furong Road, Hefei, 230601, China. FAU - Zhang, Xuan AU - Zhang X AD - Department of Clinical Pharmacology, The Second Affiliated Hospital of Anhui Medical University, No. 678 Furong Road, Hefei, 230601, China. FAU - Zhang, Qin AU - Zhang Q AD - Department of Clinical Pharmacology, The Second Affiliated Hospital of Anhui Medical University, No. 678 Furong Road, Hefei, 230601, China. FAU - Zheng, Liang AU - Zheng L AD - Department of Clinical Pharmacology, The Second Affiliated Hospital of Anhui Medical University, No. 678 Furong Road, Hefei, 230601, China. FAU - Zhou, Renpeng AU - Zhou R AD - Department of Clinical Pharmacology, The Second Affiliated Hospital of Anhui Medical University, No. 678 Furong Road, Hefei, 230601, China. FAU - Sun, Cheng AU - Sun C AD - Department of Clinical Pharmacology, The Second Affiliated Hospital of Anhui Medical University, No. 678 Furong Road, Hefei, 230601, China. FAU - Wang, Xihan AU - Wang X AD - Jiangsu Hengrui Pharmaceuticals Co., Ltd, Shanghai, China. FAU - Song, Ke AU - Song K AD - Jiangsu Hengrui Pharmaceuticals Co., Ltd, Shanghai, China. FAU - He, Zhusheng AU - He Z AD - Jiangsu Hengrui Pharmaceuticals Co., Ltd, Shanghai, China. FAU - Wang, Honghui AU - Wang H AD - Jiangsu Hengrui Pharmaceuticals Co., Ltd, Shanghai, China. FAU - Zhang, Qian AU - Zhang Q AD - Department of Clinical Pharmacology, The Second Affiliated Hospital of Anhui Medical University, No. 678 Furong Road, Hefei, 230601, China. vivian8011@163.com. FAU - Hu, Wei AU - Hu W AUID- ORCID: 0000-0002-4809-7601 AD - Department of Clinical Pharmacology, The Second Affiliated Hospital of Anhui Medical University, No. 678 Furong Road, Hefei, 230601, China. huwei@ahmu.edu.cn. LA - eng SI - ClinicalTrials.gov/NCT05274516 PT - Clinical Trial, Phase I PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20240110 PL - Switzerland TA - Clin Pharmacokinet JT - Clinical pharmacokinetics JID - 7606849 RN - 0 (Purinergic P2X Receptor Antagonists) SB - IM MH - Male MH - Humans MH - *Purinergic P2X Receptor Antagonists/adverse effects MH - Healthy Volunteers MH - *Dysgeusia MH - Dose-Response Relationship, Drug MH - Area Under Curve MH - Double-Blind Method EDAT- 2024/01/10 12:43 MHDA- 2024/03/21 12:48 CRDT- 2024/01/10 11:21 PHST- 2023/11/14 00:00 [accepted] PHST- 2024/03/21 12:48 [medline] PHST- 2024/01/10 12:43 [pubmed] PHST- 2024/01/10 11:21 [entrez] AID - 10.1007/s40262-023-01330-7 [pii] AID - 10.1007/s40262-023-01330-7 [doi] PST - ppublish SO - Clin Pharmacokinet. 2024 Mar;63(3):293-302. doi: 10.1007/s40262-023-01330-7. Epub 2024 Jan 10.