当前对小分子药物致QTc间期延长评价的探索(英文)

Current approaches to assess QTc prolongation for smallmolecule drug development

对QT间期延长的评估是小分子药物研发过程中的关键一步。ICHS7A/S7B为指导这个心血管风险评估提供了主要框架。ICH指南描述了通过体外hERG抑制、离体动作电位时间和在体心电图等三步法来评估QT间期延长。狗、猴、猪、兔、雪貂和豚鼠是常用实验动物用于体内的电生理研究,尤其使用清醒的比格犬。在这些指南中标准研究的基础上,大量新的非在体研发方法也在使用。例如受体结合对hERG抑制、离体兔子心脏或豚鼠心脏灌流等方法。这些模型和临床都有较好的相关性,并且具有成本低廉、实验周期短的特点。因此能够帮助快速准确的预测潜在的心脏病风险,从而加速小分子研发的进程。

Assessment of QTc prolongation is a critical step for small molecule drug development.ICH S7B continues to be the main frame to guide the assessment for this potential cardiovascular risk.The ICH guideline outlines a 3-step approach to QTc prolongation,including in vitro hERG inhibition,ex vivo action potential duration（APD）,and in vivo animal telemetry approach.Dog,monkey,swine,rabbit,ferret,and guinea pig are the common laboratory animals used for in vivo electrophysiology studies,especially using conscious Beagle Dog.In addition to all these guideline standard studies,many newly developed approaches,such as receptor binding for hERG inhibition,ex vivo methods such as perfused rabbit heart or guinea pig heartare are useful models for this purpose.All these methods display good correlation to clinic outcomes,and are low cost and have rapid turn-around time in nature;so that,they can help rapidly and predict this potential cardiac liability,resulting into accelerating process for small molecule drug candidate development.