Bot Corina T, Juhasz Krisztina, Haeusermann Fabian, Polonchuk Liudmila, Traebert Martin, Stoelzle-Feix Sonja
Nanion Technologies, Inc., 1 Naylon Place, Livingston, NJ 07039, USA.
Nanion Technologies GmbH, Ganghoferstrasse 70A, 80339 Munich, Germany; Institute for Nanoelectronics, Technische Universität München, Munich, Germany.
J Pharmacol Toxicol Methods. 2018 Sep-Oct;93:46-58. doi: 10.1016/j.vascn.2018.06.006. Epub 2018 Jun 22.
Since 2005 the S7B and E14 guidances from ICH and FDA have been in place to assess a potential drug candidate's ability to cause long QT syndrome. To refine these guidelines, the FDA proposed the Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative, where the assessment of drug effects on cardiac repolarization was one subject of investigation. Within the myocyte validation study, effects of pharmaceutical compounds on human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were assessed and this article will focus on the evaluation of the proarrhythmic potential of 23 blinded drugs in four hiPSC-CM cell lines.
Experiments were performed on the CardioExcyte 96 at different sites. A combined readout of contractility (via impedance) and electrophysiology endpoints (field potentials) was performed.
Our data demonstrates that hERG blockers such as dofetilide and further high risk categorized compounds prolong the field potential duration. Arrhythmia were detected in both impedance as well as field potential recordings. Intermediate risk compounds induced arrhythmia in almost all cases at the highest dose. In the case of low risk compounds, either a decrease in FPD was observed, or not a significant change from pre-addition control values.
With exceptions, hiPSC-CMs are sensitive and exhibit at least 10% delayed or shortened repolarization from pre-addition values and arrhythmia after drug application and thus can provide predictive cardiac electrophysiology data. The baseline electrophysiological parameters vary between iPS cells from different sources, therefore positive and negative control recordings are recommended.
自2005年以来，国际人用药品注册技术协调会（ICH）和美国食品药品监督管理局（FDA）的S7B和E14指南已实施，以评估潜在候选药物导致长QT综合征的能力。为完善这些指南，FDA提出了体外全面致心律失常试验（CiPA）倡议，其中药物对心脏复极化影响的评估是研究的一个主题。在心肌细胞验证研究中，评估了药物化合物对人诱导多能干细胞衍生心肌细胞（hiPSC-CMs）的影响，本文将重点评估四种hiPSC-CM细胞系中23种盲法药物的致心律失常潜力。
在不同地点使用CardioExcyte 96进行实验。对收缩性（通过阻抗）和电生理终点（场电位）进行联合读数。
我们的数据表明，多非利特等hERG阻滞剂以及其他高风险分类化合物会延长场电位持续时间。在阻抗和场电位记录中均检测到心律失常。中等风险化合物在几乎所有情况下在最高剂量时都会诱发心律失常。对于低风险化合物，要么观察到场电位持续时间缩短，要么与给药前对照值无显著变化。
除个别情况外，hiPSC-CMs敏感，给药后复极化至少比给药前值延迟或缩短10%，并出现心律失常，因此可以提供预测性心脏电生理数据。不同来源的诱导多能干细胞的基线电生理参数有所不同，因此建议进行阳性和阴性对照记录。
