全面QT/QTc研究、药物浓度QTc研究与心脏安全

Thorough-QT/QTc Study,Concentration-QTc Analysis and Cardiac Safety

非抗心律失常药物特别是抗肿瘤药物会影响心脏复极化,进而延长QT间期,导致患者出现恶性心律失常,发生心源性猝死。近年来,此类药物不良反应越来越受到监管部门、药物研发企业以及临床医生的关注。随着《E14:非抗心律失常药物QT/QTc间期延长及致心律失常潜力的临床评价》和《S7B:人用药品延迟心室复极化(QT间期延长)潜在作用的非临床评价指导原则》的发布,全面QT/QTc研究(thorough-QT/QTc study,TQT)进入了人们的视野。TQT研究在临床试验中充分评估了药物对QT间期影响的特性,为药物进入后期临床试验和上市提供了充分的临床数据,但TQT研究在实施过程中花费巨大。因此,药物浓度-QTc(concentration-QTc,C-QTc)研究被认为是更为廉价可靠的评估药物引起QT间期延长风险的模型。本文从QT间期延长的研究历史、实施、演变以及展望4个方面进行了介绍,旨在为管理者、研发者以及临床医生介绍相关概念,同时对现阶段评估药物影响QT间期的手段及其面临的挑战与应对建议提供参考。

Non-antiarrhythmic drugs,especially anti-tumor drugs,may have an impact on cardiac repolarization and prolong QT interval,leading to malignant arrhythmias and sudden cardiac death in patients.In recent years,this adverse drug reaction has attracted more and more attention from regulatory authorities,drug developers and doctors.Thorough-QT/QTc(TQT)studycame to people’s attention after the publication of ICH guidelines E14:The Interval Clinical Evaluation of QT/QTc Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs and S7B:The Non-Clinical Evaluation of the Potential for Delayed Ventricular Repolarization(QT Interval Prolongation)by Human Pharmaceuticals.TQT studies fully assess the effects of drugs on the QT interval during early phase clinical trials,providing sufficient data for late phase clinical trials and market approval.However,TQT studies are usually costly,and drug concentration-QTc(C-QTc)analysisis considered a more economicaland reliable model for evaluatingthe risk of drug-induced QT intervalprolongation.Toinform drug regulators,developers and clinical doctors,this article introduces the history,implementation,evolution and prospect of studies on QT interval prolongation,and discusses the current methods for evaluating drug impact on QT interval,their challengesand possible solutions.