升剂量犬遥测模型的特征支持将其用于 E14/S7B QT 综合风险评估。

IF 1.3 4区 医学 Q4 PHARMACOLOGY & PHARMACY Journal of pharmacological and toxicological methods Pub Date : 2024-06-06 DOI:10.1016/j.vascn.2024.107525
Alysia A. Chaves , Jude W. Ferraro , Jing Yu , Matthew J. Moye , Ka Lai Yee , Fangbiao Li , Desiree L. Steve , David J. Lengel , Christopher P. Regan
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引用次数: 0

摘要

导言:对新型化学或生物实体(NCE,NBE)的心血管效应进行非临床评估对于支持首次人体临床试验至关重要。这些评估的一个重要方面是对潜在的 QT/QTc 延长风险进行评估,因为药物引起的 QT 延长可能会造成灾难性后果。最近出版的 E14/S7B Q&As 允许在满足某些最佳实践标准的前提下,将非临床 QTc 数据作为综合风险评估的一部分纳入彻底 QT (TQT) 豁免申请。最近的出版物详细描述了从常用的拉丁方形研究设计中收集的非临床 QTc 遥测数据:为了了解来自其他遥测研究设计的数据是否足以作为 E14/S7B 综合风险评估的一部分,我们报告了升剂量遥测设计的性能和转化敏感性,以确定 QTc 延长风险的临床风险:结果:数据显示,动物体内 QTci 间期每天之间的变异性较低,这表明研究环境控制得很好,对各给药日不受控制的影响的担忧有限。以最小显著性差异(LSD)和均方根误差(RMSE)值衡量,n = 4 名受试者的递增剂量设计的历史研究方差低到足以检测到 + 10 毫秒的 QTci 间期变化,QTci 间期变化的最小可检测差异(MDD)中位数为讨论值:这些研究结果表明,递增剂量设计可以作为非临床评估 QT/QTc 延长风险和支持 TQT 豁免申请的重要工具。
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Characterization of ascending dose canine telemetry model supports its use in E14/S7B QT integrated risk assessments

Introduction

Nonclinical evaluation of the cardiovascular effects of novel chemical or biological entities (NCE, NBEs) is crucial for supporting first-in-human clinical trials. One important aspect of these evaluations is the assessment of potential QT/QTc prolongation risk, as drug-induced QT prolongation can have catastrophic effects. The recent publication of E14/S7B Q&As allows for the situational incorporation of nonclinical QTc data as part of an integrated risk assessment for a Thorough QT (TQT) waiver application provided certain best practice criteria are met. Recent publications provided detailed characterization of nonclinical QTc telemetry data collected from the commonly used Latin square study design.

Methods

To understand whether data from alternate telemetry study designs were sufficient to serve as part of the E14/S7B integrated risk assessment, we report the performance and translational sensitivity to identify clinical risk of QTc prolongation risk for an ascending dose telemetry design.

Results

The data demonstrated low variability in QTci interval within animals from day to day, indicating a well-controlled study environment and limited concern for uncontrolled effects across dosing days. Historical study variances of the ascending dose design with n = 4 subjects, measured by least significant difference (LSD) and root mean square error (RMSE) values, were low enough to detect a + 10 ms QTci interval change, and the median minimum detectable difference (MDD) for QTci interval changes was <10 ms. Furthermore, concentration-QTci (C-QTci) assessments to determine +10 ms QTci increases for known hERG inhibitors were comparable to clinical CC values listed in the E14/S7B training materials, supporting the use of the ascending dose design in an E14/S7B integrated risk assessment.

Discussion

These findings suggest that the ascending dose design can be a valuable tool in nonclinical evaluation of QT/QTc prolongation risk and the support of TQT waiver applications.

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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.
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