Qi Shen, Lingzhi Li, Weilin Qian, Xue Dong, Manchen Bao, Rong Huang, Na Li, Zi Ye, Gang Cheng, Quanren Wang, Kai Shen, Zhu Luo
{"title":"这是一项四合一的首次人体试验,目的是评估 HRS-1780(一种选择性非甾体类矿物质皮质激素受体拮抗剂)在健康男性中的安全性、耐受性、药代动力学、药效学和浓度-QTc 关系。","authors":"Qi Shen, Lingzhi Li, Weilin Qian, Xue Dong, Manchen Bao, Rong Huang, Na Li, Zi Ye, Gang Cheng, Quanren Wang, Kai Shen, Zhu Luo","doi":"10.1080/13543784.2024.2393867","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>This first-in-human study evaluated HRS-1780, an oral selective non-steroidal mineralocorticoid receptor antagonist, in healthy men.</p><p><strong>Research design and methods: </strong>In single ascending dose (SAD) part, 10 participants for each dose cohort (5, 10, 20, 40, 60, and 80 mg) were randomized (8:2) to HRS-1780 or placebo. In multiple ascending dose part, 12 participants for each dose (10, 20, and 40 mg) were randomized (9:3) to HRS-1780 or placebo once daily for 7 days. The primary endpoint was safety and tolerability.</p><p><strong>Results: </strong>HRS-1780 was well tolerated with all adverse events being mild. In the steady state, the median time to maximum concentration (T<sub>max</sub>) was 0.750 h and mean half-life was 1.76-1.96 h. High-fat/high-calorie meal prolonged T<sub>max</sub> but did not affect exposure. Multiple dosing of HRS-1780 at 40 mg showed a decreasing trend in systolic blood pressure compared with placebo. Changes in plasma aldosterone and norepinephrine with HRS-1780 were higher compared to placebo. Upper bounds of two-sided 90% confidence interval of placebo-adjusted change-from-baseline QTcF were below 10 msec at the maximum concentration in SAD. The trial had limited sample size and short study duration.</p><p><strong>Conclusions: </strong>HRS-1780 had favorable safety and pharmacokinetic profiles and did not cause clinically meaningful QTcF prolongation.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov (NCT05638126).</p>","PeriodicalId":12313,"journal":{"name":"Expert opinion on investigational drugs","volume":null,"pages":null},"PeriodicalIF":4.9000,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"A four-in-one first-in-human study to assess safety, tolerability, pharmacokinetics, pharmacodynamics, and concentration-QTc relationship of HRS-1780, a selective non-steroidal mineralocorticoid receptor antagonist, in healthy men.\",\"authors\":\"Qi Shen, Lingzhi Li, Weilin Qian, Xue Dong, Manchen Bao, Rong Huang, Na Li, Zi Ye, Gang Cheng, Quanren Wang, Kai Shen, Zhu Luo\",\"doi\":\"10.1080/13543784.2024.2393867\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>This first-in-human study evaluated HRS-1780, an oral selective non-steroidal mineralocorticoid receptor antagonist, in healthy men.</p><p><strong>Research design and methods: </strong>In single ascending dose (SAD) part, 10 participants for each dose cohort (5, 10, 20, 40, 60, and 80 mg) were randomized (8:2) to HRS-1780 or placebo. In multiple ascending dose part, 12 participants for each dose (10, 20, and 40 mg) were randomized (9:3) to HRS-1780 or placebo once daily for 7 days. The primary endpoint was safety and tolerability.</p><p><strong>Results: </strong>HRS-1780 was well tolerated with all adverse events being mild. In the steady state, the median time to maximum concentration (T<sub>max</sub>) was 0.750 h and mean half-life was 1.76-1.96 h. High-fat/high-calorie meal prolonged T<sub>max</sub> but did not affect exposure. Multiple dosing of HRS-1780 at 40 mg showed a decreasing trend in systolic blood pressure compared with placebo. Changes in plasma aldosterone and norepinephrine with HRS-1780 were higher compared to placebo. Upper bounds of two-sided 90% confidence interval of placebo-adjusted change-from-baseline QTcF were below 10 msec at the maximum concentration in SAD. The trial had limited sample size and short study duration.</p><p><strong>Conclusions: </strong>HRS-1780 had favorable safety and pharmacokinetic profiles and did not cause clinically meaningful QTcF prolongation.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov (NCT05638126).</p>\",\"PeriodicalId\":12313,\"journal\":{\"name\":\"Expert opinion on investigational drugs\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":4.9000,\"publicationDate\":\"2024-10-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Expert opinion on investigational drugs\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1080/13543784.2024.2393867\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/8/26 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"PHARMACOLOGY & PHARMACY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Expert opinion on investigational drugs","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1080/13543784.2024.2393867","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/8/26 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
A four-in-one first-in-human study to assess safety, tolerability, pharmacokinetics, pharmacodynamics, and concentration-QTc relationship of HRS-1780, a selective non-steroidal mineralocorticoid receptor antagonist, in healthy men.
Background: This first-in-human study evaluated HRS-1780, an oral selective non-steroidal mineralocorticoid receptor antagonist, in healthy men.
Research design and methods: In single ascending dose (SAD) part, 10 participants for each dose cohort (5, 10, 20, 40, 60, and 80 mg) were randomized (8:2) to HRS-1780 or placebo. In multiple ascending dose part, 12 participants for each dose (10, 20, and 40 mg) were randomized (9:3) to HRS-1780 or placebo once daily for 7 days. The primary endpoint was safety and tolerability.
Results: HRS-1780 was well tolerated with all adverse events being mild. In the steady state, the median time to maximum concentration (Tmax) was 0.750 h and mean half-life was 1.76-1.96 h. High-fat/high-calorie meal prolonged Tmax but did not affect exposure. Multiple dosing of HRS-1780 at 40 mg showed a decreasing trend in systolic blood pressure compared with placebo. Changes in plasma aldosterone and norepinephrine with HRS-1780 were higher compared to placebo. Upper bounds of two-sided 90% confidence interval of placebo-adjusted change-from-baseline QTcF were below 10 msec at the maximum concentration in SAD. The trial had limited sample size and short study duration.
Conclusions: HRS-1780 had favorable safety and pharmacokinetic profiles and did not cause clinically meaningful QTcF prolongation.
期刊介绍:
Expert Opinion on Investigational Drugs (ISSN 1354-3784 [print], 1744-7658 [electronic]) is a MEDLINE-indexed, peer-reviewed, international journal publishing review articles and original papers on drugs in preclinical and early stage clinical development, providing expert opinion on the scope for future development.
The Editors welcome:
Reviews covering preclinical through to Phase II data on drugs or drug classes for specific indications, and their potential impact on future treatment strategies
Drug Evaluations reviewing the clinical and pharmacological data on a particular drug
Original Research papers reporting the results of clinical investigations on agents that are in Phase I and II clinical trials
The audience consists of scientists, managers and decision-makers in the pharmaceutical industry, and others closely involved in R&D.