Proarrhythmia liability assessment and the comprehensive in vitro Proarrhythmia Assay (CiPA): An industry survey on current practice
Proarrhythmia liability assessment and the comprehensive in vitro Proarrhythmia Assay (CiPA): An industry survey on current practice
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DOI：
10.1016/j.vascn.2017.02.021
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发表时间：
2017-07-01
影响因子：
1.9
通讯作者：
Curtis, Michael J.
中科院分区：
文献类型：
--
作者：
Authier, Simon;Pugsley, Michael K.;Curtis, Michael J.
简介：安全药理学学会（SPS）对其成员进行了一项调查，以确定与综合体外致心律失常试验（CiPA）中考虑的测试相关的行业实践。方法：调查主题包括解决致心律失常问题的非临床方法、计算机模拟研究的进行、使用的体外离子通道测试方法、在心脏离子通道研究进行期间用作阳性对照的药物，在非临床研究中观察到的心律失常的类型和预期的CiPA离子通道assay.Results的使用：在计算机模拟研究被用来评估只有15%的响应者对心室动作电位的影响。体外试验主要用于评估QT延长（95%）、心脏Ca2+和Na+通道阻滞（82%）和QT缩短或QRS延长（53%）。为了降低致心律失常候选药物的风险，最常使用的那些与CiPA最相关的测定，包括用于确定药物阻断效力的稳定表达离子通道的细胞系（89%）和人干细胞衍生的或诱导的多能干细胞心肌细胞（46%）。与一般致心律失常去风险相关的体内试验包括使用植入式遥测技术（88%）、带护套的外部遥测（62%）和麻醉动物模型（53%）记录ECG。虽然CiPA initiativewas支持92%的应答者，可能有一些目前的做法和未来的期望之间的脱节，作为explained.Discussion：在药物开发的致心律失常的责任评估目前包括研究类型与CiPA一致。预计CiPA将发展成为一个可行的解决方案，以解决心律失常责任测试仍然不理想的问题。(C)2017作者爱思唯尔公司出版
Introduction: The Safety Pharmacology Society (SPS) has conducted a survey of itsmembership to identify industry practices related to testing considered in the Comprehensive In vitro Proarrhythmia Assay (CiPA).Methods: Survey topics included nonclinical approaches to address proarrhythmia issues, conduct of in silico studies, in vitro ion channel testing methods used, drugs used as positive controls during the conduct of cardiac ion channel studies, types of arrhythmias observed in non-clinical studies and use of the anticipated CiPA ion channel assay.Results: In silico studies were used to evaluate effects on ventricular action potentials by only 15% of responders. In vitro assays were used mostly to assess QT prolongation (95%), cardiac Ca2+ and Na+ channel blockade (82%) and QT shortening or QRS prolongation (53%). For de-risking of candidate drugs for proarrhythmia, those assays most relevant to CiPA including cell lines stably expressing ion channels used to determine potency of drug block were most frequently used (89%) and human stemcell-derived or induced pluripotent stemcell cardiomyocytes (46%). Those in vivo assays related to general proarrhythmia derisking include ECG recording using implanted telemetry technology (88%), jacketed external telemetry (62%) and anesthetized animal models (53%). While the CiPA initiativewas supported by 92% of responders, there may be some disconnect between current practice and future expectations, as explained.Discussion: Proarrhythmia liability assessment in drug development presently includes study types consistent with CiPA. It is anticipated that CiPA will develop into a workable solution to the concern that proarrhythmia liability testing remains suboptimal. (C) 2017 The Authors. Published by Elsevier Inc.