Best practice considerations for nonclinical in vivo cardiovascular telemetry studies in non-rodent species: Delivering high quality QTc data to support ICH E14/S7B Q&As

IF 1.3 4区 医学 Q4 PHARMACOLOGY & PHARMACY
Eric I. Rossman , Todd A. Wisialowski , Hugo M. Vargas , Jean-Pierre Valentin , Michael G. Rolf , Brian M. Roche , Steve Riley , Michael K. Pugsley , Jill Nichols , Dingzhou Li , Derek J. Leishman , Robert B. Kleiman , Andrea Greiter-Wilke , Gary A. Gintant , Michael J. Engwall , Annie Delaunois , Simon Authier
{"title":"Best practice considerations for nonclinical in vivo cardiovascular telemetry studies in non-rodent species: Delivering high quality QTc data to support ICH E14/S7B Q&As","authors":"Eric I. Rossman ,&nbsp;Todd A. Wisialowski ,&nbsp;Hugo M. Vargas ,&nbsp;Jean-Pierre Valentin ,&nbsp;Michael G. Rolf ,&nbsp;Brian M. Roche ,&nbsp;Steve Riley ,&nbsp;Michael K. Pugsley ,&nbsp;Jill Nichols ,&nbsp;Dingzhou Li ,&nbsp;Derek J. Leishman ,&nbsp;Robert B. Kleiman ,&nbsp;Andrea Greiter-Wilke ,&nbsp;Gary A. Gintant ,&nbsp;Michael J. Engwall ,&nbsp;Annie Delaunois ,&nbsp;Simon Authier","doi":"10.1016/j.vascn.2023.107270","DOIUrl":null,"url":null,"abstract":"<div><p>The ICH E14/S7B Questions and Answers (Q&amp;As) guideline introduces the concept of a “double negative” nonclinical scenario (negative hERG assay and negative in vivo QTc study) to demonstrate that a drug does not produce a clinically relevant QT prolongation<span><span><span> (i.e., no QT liability). This nonclinical “double negative” data package, along with negative Phase 1 clinical QTc data, may be sufficient to substitute for a clinical Thorough QT (TQT) study in some specific cases. While standalone GLP in vivo cardiovascular studies in non-rodent species are standard practice during nonclinical drug development for small molecule programs, a variety of approaches to the design, conduct, analysis and interpretation are utilized across pharmaceutical companies and </span>contract research organizations (CROs) that may, in some cases, negatively impact the stringent sensitivity needed to fulfill the new Q&amp;As. Subject matter experts from both Pharma and CROs have collaborated to recommend best practices for more robust nonclinical cardiovascular telemetry studies in non-rodent species, with input from clinical and regulatory experts. The aim was to increase consistency and harmonization across the industry and to ensure delivery of high quality nonclinical QTc data to meet the proposed sensitivities defined within the revised ICH E14/S7B Q&amp;As guideline (Q&amp;As 5.1 and 6.1). The detailed best practice recommendations presented here cover the design and execution of the </span>safety pharmacology<span> cardiovascular study, including optimal methods for acquiring, analyzing, reporting, and interpreting the resulting QTc and pharmacokinetic data to allow for direct comparison to clinical exposures and assessment of safety margin for QTc prolongation.</span></span></p></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":null,"pages":null},"PeriodicalIF":1.3000,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"2","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of pharmacological and toxicological methods","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S1056871923000217","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q4","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
引用次数: 2

Abstract

The ICH E14/S7B Questions and Answers (Q&As) guideline introduces the concept of a “double negative” nonclinical scenario (negative hERG assay and negative in vivo QTc study) to demonstrate that a drug does not produce a clinically relevant QT prolongation (i.e., no QT liability). This nonclinical “double negative” data package, along with negative Phase 1 clinical QTc data, may be sufficient to substitute for a clinical Thorough QT (TQT) study in some specific cases. While standalone GLP in vivo cardiovascular studies in non-rodent species are standard practice during nonclinical drug development for small molecule programs, a variety of approaches to the design, conduct, analysis and interpretation are utilized across pharmaceutical companies and contract research organizations (CROs) that may, in some cases, negatively impact the stringent sensitivity needed to fulfill the new Q&As. Subject matter experts from both Pharma and CROs have collaborated to recommend best practices for more robust nonclinical cardiovascular telemetry studies in non-rodent species, with input from clinical and regulatory experts. The aim was to increase consistency and harmonization across the industry and to ensure delivery of high quality nonclinical QTc data to meet the proposed sensitivities defined within the revised ICH E14/S7B Q&As guideline (Q&As 5.1 and 6.1). The detailed best practice recommendations presented here cover the design and execution of the safety pharmacology cardiovascular study, including optimal methods for acquiring, analyzing, reporting, and interpreting the resulting QTc and pharmacokinetic data to allow for direct comparison to clinical exposures and assessment of safety margin for QTc prolongation.

非啮齿类动物非临床体内心血管遥测研究的最佳实践考虑:提供高质量的QTc数据以支持ICH E14/S7B q&a。
ICH E14/S7B问答(Q&As)指南引入了“双阴性”非临床情况(hERG检测阴性和体内QTc研究阴性)的概念,以证明药物不会产生临床相关的QT延长(即无QT责任)。这种非临床“双阴性”数据包,以及阴性的1期临床QTc数据,可能足以替代某些特定病例的临床全面QT (TQT)研究。虽然独立的GLP在非啮齿类动物体内心血管研究是小分子项目非临床药物开发过程中的标准做法,但制药公司和合同研究组织(cro)采用了各种设计、实施、分析和解释的方法,在某些情况下,这些方法可能会对满足新问答所需的严格灵敏度产生负面影响。来自制药公司和cro的主题专家合作,在临床和监管专家的投入下,为非啮齿动物物种的非临床心血管遥测研究推荐了最佳实践。目的是提高整个行业的一致性和协调性,并确保提供高质量的非临床QTc数据,以满足修订后的ICH E14/S7B Q&As指南(Q&As 5.1和6.1)中提议的敏感性定义。本文提出的详细最佳实践建议涵盖了心血管安全药理学研究的设计和执行,包括获取、分析、报告和解释结果QTc和药代动力学数据的最佳方法,以便与临床暴露进行直接比较,并评估延长QTc的安全裕度。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
Journal of pharmacological and toxicological methods
Journal of pharmacological and toxicological methods PHARMACOLOGY & PHARMACY-TOXICOLOGY
CiteScore
3.60
自引率
10.50%
发文量
56
审稿时长
26 days
期刊介绍: Journal of Pharmacological and Toxicological Methods publishes original articles on current methods of investigation used in pharmacology and toxicology. Pharmacology and toxicology are defined in the broadest sense, referring to actions of drugs and chemicals on all living systems. With its international editorial board and noted contributors, Journal of Pharmacological and Toxicological Methods is the leading journal devoted exclusively to experimental procedures used by pharmacologists and toxicologists.
×
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