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。

IF 4.9 2区 医学 Q1 PHARMACOLOGY & PHARMACY
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}
引用次数: 0

摘要

研究背景这项首次人体研究评估了健康男性口服选择性非甾体类矿化皮质激素受体拮抗剂HRS-1780的疗效:在单次递增剂量(SAD)部分,每个剂量组群(5、10、20、40、60和80毫克)的10名参与者被随机(8:2)分配到HRS-1780或安慰剂中。在多剂量递增部分,每个剂量组(10、20和40毫克)的12名参与者以9:3的比例随机接受HRS-1780或安慰剂治疗,每天一次,连续治疗7天。主要终点是安全性和耐受性:结果:HRS-1780耐受性良好,所有不良反应均较轻微。稳态时,达到最大浓度(Tmax)的中位时间为0.750小时,平均半衰期为1.76-1.96小时。高脂肪/高热量膳食会延长Tmax,但不会影响暴露量。与安慰剂相比,多次服用40毫克HRS-1780后收缩压呈下降趋势。与安慰剂相比,HRS-1780 对血浆醛固酮和去甲肾上腺素的影响更大。在SAD的最大浓度下,安慰剂调整后的基线QTcF变化的双侧90%置信区间上限低于10毫秒。该试验的样本量有限,研究持续时间较短:HRS-1780具有良好的安全性和药代动力学特征,不会导致有临床意义的QTcF延长:试验注册::ClinicalTrials.gov (NCT05638126)。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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.

Trial registration: ClinicalTrials.gov (NCT05638126).

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
CiteScore
10.00
自引率
0.00%
发文量
71
审稿时长
6-12 weeks
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.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信