Cardiac Safety Services, QuintilesIMS, 4820 Emperor Blvd, Durham, NC 27703, USA.
Cardiac Safety Services, QuintilesIMS, 602 Western Express Highway, Andheri East, Mumbai 400 069, Maharashtra, India.
Eur Heart J Cardiovasc Pharmacother. 2017 Apr 1;3(2):118-124. doi: 10.1093/ehjcvp/pvw045.
Following marketing withdrawals of several drugs due to proarrhythmic safety concerns, the ICH Guidelines S7B and E14 were released in 2005 and have guided pre-approval cardiac safety assessments in multiple regulatory jurisdictions. While this S7B-E14 paradigm has successfully prevented drugs with unanticipated potential for inducing Torsades de Pointes entering the market, it has unintentionally resulted in the termination of development programs for potentially important compounds that could have exhibited a favourable benefit-risk balance. The Comprehensive In vitro Proarrhythmia Assay paradigm is currently attracting considerable attention as a solution to this problem. While much evaluative work in this new paradigm will be conducted in the non-clinical domain, human electrocardiographic assessments will remain an important component of the overall investigational strategy, possibly being conducted in Phase I trials employing exposure-response modelling. This article reviews recent developments in proarrhythmic cardiac safety assessments of new drugs, their rationales, and current limitations.
由于致心律失常的安全性问题，一些药物在市场推广后被撤出，ICH 指南 S7B 和 E14 于 2005 年发布，并指导了多个监管管辖区的新药审批前心脏安全性评估。虽然这一 S7B-E14 模式成功地阻止了具有不可预见的尖端扭转型室性心动过速诱导潜力的药物进入市场，但它也无意中导致了具有潜在重要化合物的开发计划的终止，这些化合物可能表现出有利的风险效益平衡。综合体外致心律失常性检测方法目前正作为解决这一问题的一种方法而受到广泛关注。虽然在这个新的模式下会在非临床领域进行大量评估工作，但人体心电图评估仍将是整体研究策略的一个重要组成部分，可能会在采用暴露-反应建模的 I 期临床试验中进行。本文综述了新药致心律失常性心脏安全性评估的最新进展、其基本原理和当前的局限性。
