Delpy Eric, Bétat Anne-Marie, Delaunois Annie, Drieu la Rochelle Christophe, Martel Eric, Valentin Jean-Pierre
Non-Clinical Department, Biotrial Pharmacology, Rennes, France.
Early Clinical Development & Translational Science, UCB, Braine-l'Alleud, Belgium.
J Pharmacokinet Pharmacodyn. 2025 May 16;52(3):32. doi: 10.1007/s10928-025-09979-2.
The assessment of drug-induced QT interval prolongation and associated proarrhythmic risks, such as Torsades de Pointes (TdP), has evolved significantly over the past decades. This review traces the development of nonclinical QT evaluation, highlighting key milestones and innovations that have shaped current practices in cardiac safety assessment. The emergence of regulatory guidelines, including International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) S7B, established a nonclinical framework for evaluating drug effects on cardiac repolarization, addressing concerns raised by drug withdrawals in the 1990s. Advances in in vitro, in vivo, and in silico models have enhanced the predictive accuracy of nonclinical studies, with the hERG assay and telemetry-based animal models becoming gold standards. Recent initiatives, such as the Comprehensive in vitro Proarrhythmia Assay (CiPA) and the Japan iPS Cardiac Safety Assessment (JiCSA), emphasize integrating mechanistic insights from human-derived cardiomyocyte models and computational approaches to refine risk predictions. The 2020s mark a shift toward integrated nonclinical-clinical risk assessments, as exemplified by the ICH E14/S7B Questions and Answers. These highlight the need of best practices for study design, data analysis, and interpretation to support regulatory decision-making. Furthermore, the adoption of New Approach Methodologies (NAMs) and reinforced adherence to 3Rs principles (Reduce, Refine, Replace) reflect a commitment to ethical and innovative safety science. This review underscores the importance of harmonized and translational approaches in cardiac safety evaluation, providing a foundation for advancing drug development while safeguarding patient safety. Future directions include further integration of advanced methodologies and regulatory harmonization to streamline nonclinical and clinical risk assessments.
在过去几十年中，药物诱导的QT间期延长及相关心律失常风险（如尖端扭转型室性心动过速（TdP））的评估方法有了显著发展。本综述追溯了非临床QT评估的发展历程，重点介绍了塑造当前心脏安全性评估实践的关键里程碑和创新成果。包括人用药品注册技术国际协调理事会（ICH）S7B在内的监管指南的出台，建立了一个评估药物对心脏复极影响的非临床框架，解决了20世纪90年代因药物撤市引发的问题。体外、体内和计算机模型的进展提高了非临床研究的预测准确性，其中hERG检测和基于遥测技术的动物模型成为了金标准。近期的一些举措，如全面体外心律失常检测（CiPA）和日本诱导多能干细胞心脏安全性评估（JiCSA），强调整合源自人类心肌细胞模型的机制性见解和计算方法，以优化风险预测。21世纪20年代标志着向综合非临床 - 临床风险评估的转变，如ICH E14/S7B问答所示。这些突出了研究设计、数据分析和解释的最佳实践对于支持监管决策的必要性。此外，采用新方法学（NAMs）并强化对3R原则（减少、优化、替代）的遵守，体现了对道德和创新安全科学的承诺。本综述强调了心脏安全性评估中协调一致和转化方法的重要性，为推进药物研发同时保障患者安全奠定了基础。未来的方向包括进一步整合先进方法和监管协调，以简化非临床和临床风险评估。
