在健康受试者中,采用鸡尾酒法,选择性食欲素-1受体拮抗剂尼瓦松(ACT-539313)在体外和体内对多种细胞色素P450探针底物的影响。

IF 2.9 4区 医学 Q2 PHARMACOLOGY & PHARMACY
Benjamin Berger, Priska Kaufmann, Matthias Berse, Alexander Treiber, Nathalie Grignaschi, Jasper Dingemanse
{"title":"在健康受试者中,采用鸡尾酒法,选择性食欲素-1受体拮抗剂尼瓦松(ACT-539313)在体外和体内对多种细胞色素P450探针底物的影响。","authors":"Benjamin Berger,&nbsp;Priska Kaufmann,&nbsp;Matthias Berse,&nbsp;Alexander Treiber,&nbsp;Nathalie Grignaschi,&nbsp;Jasper Dingemanse","doi":"10.1002/prp2.1143","DOIUrl":null,"url":null,"abstract":"<p><p>Nivasorexant, a selective orexin-1-receptor antagonist, has recently been assessed in the treatment of humans with binge-eating disorder. Herein, the inhibitory potential of nivasorexant on cytochromes P450 (CYPs) 2C9, 2C19, and 3A4 was evaluated. Human liver microsomes/recombinant CYP enzymes were evaluated in vitro. In vivo, a single-center, open-label, fixed-sequence study was performed in healthy adults to explore the effect of 100 mg nivasorexant administered twice daily (b.i.d.) on the pharmacokinetics (PK) of flurbiprofen (50 mg, CYP2C9), omeprazole (20 mg, CYP2C19), midazolam (2 mg, CYP3A4) making use of a cocktail approach. Plasma PK sampling was performed over 24 h on Day 1 (Cocktail alone), 8 (Cocktail + nivasorexant), and 15 (Cocktail + nivasorexant at steady state). Genotyping of subjects' CYPs was performed while safety and tolerability were also assessed. In vitro, nivasorexant inhibited CYP2C9, 2C19, and 3A4 in competitive inhibition assays with IC<sub>50</sub> values of 8.6, 1.6, and 19-44 μM, respectively, while showing a significant time-dependent CYP2C19 inhibition. In 22 subjects, exposure to flurbiprofen, omeprazole, and midazolam was generally higher during concomitant single- (i.e., area under the plasma concentration-time curve [AUC] ratio increased by 1.04-, 2.05-, and 1.56-fold, respectively) and repeated-dose (i.e., AUC ratio increased by 1.47-, 6.84-, and 3.71-fold, respectively) nivasorexant administration compared with the cocktail substrates administered alone. The most frequently reported adverse event was somnolence. According to regulatory guidance, nivasorexant is classified as a moderate CYP2C19 and weak CYP3A4 inhibitor after 1 day and as a weak CYP2C9, strong CYP2C19, and moderate CYP3A4 inhibitor after 8 days of 100 mg b.i.d. administration. Clinicaltrials.gov ID: NCT05254548.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":null,"pages":null},"PeriodicalIF":2.9000,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/11/83/PRP2-11-e01143.PMC10557102.pdf","citationCount":"0","resultStr":"{\"title\":\"Effect of nivasorexant (ACT-539313), a selective orexin-1-receptor antagonist, on multiple cytochrome P450 probe substrates in vitro and in vivo using a cocktail approach in healthy subjects.\",\"authors\":\"Benjamin Berger,&nbsp;Priska Kaufmann,&nbsp;Matthias Berse,&nbsp;Alexander Treiber,&nbsp;Nathalie Grignaschi,&nbsp;Jasper Dingemanse\",\"doi\":\"10.1002/prp2.1143\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Nivasorexant, a selective orexin-1-receptor antagonist, has recently been assessed in the treatment of humans with binge-eating disorder. Herein, the inhibitory potential of nivasorexant on cytochromes P450 (CYPs) 2C9, 2C19, and 3A4 was evaluated. Human liver microsomes/recombinant CYP enzymes were evaluated in vitro. In vivo, a single-center, open-label, fixed-sequence study was performed in healthy adults to explore the effect of 100 mg nivasorexant administered twice daily (b.i.d.) on the pharmacokinetics (PK) of flurbiprofen (50 mg, CYP2C9), omeprazole (20 mg, CYP2C19), midazolam (2 mg, CYP3A4) making use of a cocktail approach. Plasma PK sampling was performed over 24 h on Day 1 (Cocktail alone), 8 (Cocktail + nivasorexant), and 15 (Cocktail + nivasorexant at steady state). Genotyping of subjects' CYPs was performed while safety and tolerability were also assessed. In vitro, nivasorexant inhibited CYP2C9, 2C19, and 3A4 in competitive inhibition assays with IC<sub>50</sub> values of 8.6, 1.6, and 19-44 μM, respectively, while showing a significant time-dependent CYP2C19 inhibition. In 22 subjects, exposure to flurbiprofen, omeprazole, and midazolam was generally higher during concomitant single- (i.e., area under the plasma concentration-time curve [AUC] ratio increased by 1.04-, 2.05-, and 1.56-fold, respectively) and repeated-dose (i.e., AUC ratio increased by 1.47-, 6.84-, and 3.71-fold, respectively) nivasorexant administration compared with the cocktail substrates administered alone. The most frequently reported adverse event was somnolence. According to regulatory guidance, nivasorexant is classified as a moderate CYP2C19 and weak CYP3A4 inhibitor after 1 day and as a weak CYP2C9, strong CYP2C19, and moderate CYP3A4 inhibitor after 8 days of 100 mg b.i.d. administration. Clinicaltrials.gov ID: NCT05254548.</p>\",\"PeriodicalId\":19948,\"journal\":{\"name\":\"Pharmacology Research & Perspectives\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":2.9000,\"publicationDate\":\"2023-10-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/11/83/PRP2-11-e01143.PMC10557102.pdf\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Pharmacology Research & Perspectives\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1002/prp2.1143\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"PHARMACOLOGY & PHARMACY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Pharmacology Research & Perspectives","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1002/prp2.1143","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
引用次数: 0

摘要

Nivasorexant是一种选择性食欲素-1受体拮抗剂,最近被评估用于治疗人类暴饮性饮食障碍。在此,评估了尼瓦松对细胞色素P450(CYPs)2C9、2C19和3A4的抑制潜力。在体外评估人肝微粒体/重组CYP酶。在体内,对健康成年人进行了一项单中心、开放标签、固定序列的研究,以探索100 mg nivasorexant,每日两次(b.i.d.)对氟比洛芬(50 mg,CYP2C9),奥美拉唑(20 mg,CYP2C19),咪唑安定(2 mg、CYP3A4)。在24小时内进行血浆PK取样 第1天的h(单独的鸡尾酒)、第8天(鸡尾酒+nivasorexant)和第15天(稳定状态下的鸡尾酒+niwasorexat)。对受试者的CYP进行基因分型,同时评估安全性和耐受性。在体外,nivasorexant在竞争性抑制试验中抑制CYP2C9、2C19和3A4,IC50值分别为8.6、1.6和19-44 μM,同时显示出显著的时间依赖性CYP2C19抑制。在22名受试者中,与单独给药的鸡尾酒底物相比,咪达唑仑在伴随单次给药(即,血浆浓度-时间曲线下面积[AUC]比分别增加1.04倍、2.05倍和1.56倍)和重复给药(AUC比分别增加1.47倍、6.84倍和3.71倍)期间通常更高。最常见的不良事件是嗜睡。根据监管指南,nivasorexant在1天后被分类为中度CYP2C19和弱CYP3A4抑制剂,在8天后被归类为弱CYP2C9、强CYP2C19或中度CYP3A4抑制物 100天 mg b.i.d.给药。Clinicaltrials.gov ID:NCT05254548。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Effect of nivasorexant (ACT-539313), a selective orexin-1-receptor antagonist, on multiple cytochrome P450 probe substrates in vitro and in vivo using a cocktail approach in healthy subjects.

Effect of nivasorexant (ACT-539313), a selective orexin-1-receptor antagonist, on multiple cytochrome P450 probe substrates in vitro and in vivo using a cocktail approach in healthy subjects.

Effect of nivasorexant (ACT-539313), a selective orexin-1-receptor antagonist, on multiple cytochrome P450 probe substrates in vitro and in vivo using a cocktail approach in healthy subjects.

Effect of nivasorexant (ACT-539313), a selective orexin-1-receptor antagonist, on multiple cytochrome P450 probe substrates in vitro and in vivo using a cocktail approach in healthy subjects.

Nivasorexant, a selective orexin-1-receptor antagonist, has recently been assessed in the treatment of humans with binge-eating disorder. Herein, the inhibitory potential of nivasorexant on cytochromes P450 (CYPs) 2C9, 2C19, and 3A4 was evaluated. Human liver microsomes/recombinant CYP enzymes were evaluated in vitro. In vivo, a single-center, open-label, fixed-sequence study was performed in healthy adults to explore the effect of 100 mg nivasorexant administered twice daily (b.i.d.) on the pharmacokinetics (PK) of flurbiprofen (50 mg, CYP2C9), omeprazole (20 mg, CYP2C19), midazolam (2 mg, CYP3A4) making use of a cocktail approach. Plasma PK sampling was performed over 24 h on Day 1 (Cocktail alone), 8 (Cocktail + nivasorexant), and 15 (Cocktail + nivasorexant at steady state). Genotyping of subjects' CYPs was performed while safety and tolerability were also assessed. In vitro, nivasorexant inhibited CYP2C9, 2C19, and 3A4 in competitive inhibition assays with IC50 values of 8.6, 1.6, and 19-44 μM, respectively, while showing a significant time-dependent CYP2C19 inhibition. In 22 subjects, exposure to flurbiprofen, omeprazole, and midazolam was generally higher during concomitant single- (i.e., area under the plasma concentration-time curve [AUC] ratio increased by 1.04-, 2.05-, and 1.56-fold, respectively) and repeated-dose (i.e., AUC ratio increased by 1.47-, 6.84-, and 3.71-fold, respectively) nivasorexant administration compared with the cocktail substrates administered alone. The most frequently reported adverse event was somnolence. According to regulatory guidance, nivasorexant is classified as a moderate CYP2C19 and weak CYP3A4 inhibitor after 1 day and as a weak CYP2C9, strong CYP2C19, and moderate CYP3A4 inhibitor after 8 days of 100 mg b.i.d. administration. Clinicaltrials.gov ID: NCT05254548.

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
Pharmacology Research & Perspectives
Pharmacology Research & Perspectives Pharmacology, Toxicology and Pharmaceutics-General Pharmacology, Toxicology and Pharmaceutics
CiteScore
5.30
自引率
3.80%
发文量
120
审稿时长
20 weeks
期刊介绍: PR&P is jointly published by the American Society for Pharmacology and Experimental Therapeutics (ASPET), the British Pharmacological Society (BPS), and Wiley. PR&P is a bi-monthly open access journal that publishes a range of article types, including: target validation (preclinical papers that show a hypothesis is incorrect or papers on drugs that have failed in early clinical development); drug discovery reviews (strategy, hypotheses, and data resulting in a successful therapeutic drug); frontiers in translational medicine (drug and target validation for an unmet therapeutic need); pharmacological hypotheses (reviews that are oriented to inform a novel hypothesis); and replication studies (work that refutes key findings [failed replication] and work that validates key findings). PR&P publishes papers submitted directly to the journal and those referred from the journals of ASPET and the BPS
×
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