改进体内QTc测定:实施最佳实践以支持综合非临床临床QTc风险评估和TQT替代品的价值

IF 1.3 4区 医学 Q4 PHARMACOLOGY & PHARMACY Journal of pharmacological and toxicological methods Pub Date : 2023-05-01 DOI:10.1016/j.vascn.2023.107265
Hugo M. Vargas , Eric I. Rossman , Todd A. Wisialowski , Jill Nichols , Michael K. Pugsley , Brian Roche , Gary A. Gintant , Andrea Greiter-Wilke , Robert B. Kleiman , Jean-Pierre Valentin , Derek J. Leishman
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引用次数: 2

摘要

临床ICH E14和非临床ICH S7B指南的最新更新和修改都与药物诱导的延迟复极风险评估有关,为非临床体内心电图(ECG)数据直接影响临床策略、解释、监管决策和产品标签提供了机会。基于共识标准化协议和实验最佳实践的更稳健的非临床体内QTc数据集可以利用这一机会,减少变异性并优化QTc信号检测,即证明测定灵敏度。此类非临床研究的直接机会是当不能安全地实现足够的临床暴露(例如超治疗性),或者其他因素限制了临床QTc评估的稳健性时,例如ICH E14 Q5.1和Q6.1场景。这篇立场论文讨论了导致这一机会的监管历史演变和过程,并详细介绍了对未来候选新药非临床体内QTc研究的期望。一致设计、执行和分析的体内QTc测定将带来可靠的解释,并增加其在临床QTc风险评估中的价值。最后,本文为我们的配套文章提供了基本原理和依据,该文章描述了体内QTc最佳实践的技术细节,并提出了实现新ICH E14/S7B Q&;如,见Rossman等人,2023(本期刊)。
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Improving the in Vivo QTc assay: The value of implementing best practices to support an integrated nonclinical-clinical QTc risk assessment and TQT substitute

Recent updates and modifications to the clinical ICH E14 and nonclinical ICH S7B guidelines, which both relate to the evaluation of drug-induced delayed repolarization risk, provide an opportunity for nonclinical in vivo electrocardiographic (ECG) data to directly influence clinical strategies, interpretation, regulatory decision-making and product labeling. This opportunity can be leveraged with more robust nonclinical in vivo QTc datasets based upon consensus standardized protocols and experimental best practices that reduce variability and optimize QTc signal detection, i.e., demonstrate assay sensitivity. The immediate opportunity for such nonclinical studies is when adequate clinical exposures (e.g., supratherapeutic) cannot be safely achieved, or other factors limit the robustness of the clinical QTc evaluation, e.g., the ICH E14 Q5.1 and Q6.1 scenarios. This position paper discusses the regulatory historical evolution and processes leading to this opportunity and details the expectations of future nonclinical in vivo QTc studies of new drug candidates. The conduct of in vivo QTc assays that are consistently designed, executed and analyzed will lead to confident interpretation, and increase their value for clinical QTc risk assessment. Lastly, this paper provides the rationale and basis for our companion article which describes technical details on in vivo QTc best practices and recommendations to achieve the goals of the new ICH E14/S7B Q&As, see Rossman et al., 2023 (this journal).

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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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