CSAHi study: Evaluation of multi-electrode array in combination with human iPS cell-derived cardiomyocytes to predict drug-induced QT prolongation and arrhythmia - Effects of 7 reference compounds at 10 facilities
CSAHi study: Evaluation of multi-electrode array in combination with human iPS cell-derived cardiomyocytes to predict drug-induced QT prolongation and arrhythmia - Effects of 7 reference compounds at 10 facilities
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DOI：
10.1016/j.vascn.2015.12.002
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发表时间：
2016-03-01
影响因子：
1.9
通讯作者：
Miyamoto, Norimasa
中科院分区：
文献类型：
--
作者：
Kitaguchi, Takashi;Moriyama, Yuta;Miyamoto, Norimasa
药物性QT间期延长是药物开发过程中的一个主要安全问题，因为它可能导致致命性室性心律失常。在这项研究中，我们评估了人类诱导的多能干细胞来源的心肌细胞（hiPS-CMs）的多电极阵列（MEA）在预测药物诱导的QT延长和心律失常方面的效用。方法：10家机构采用MED64 MEA系统和市售hiPS-CMs对7种参比药物（E-4031、莫西沙星、氟卡奈德、特非那定、氯胺醇293B、维拉帕米和阿司匹林）的疗效进行评价。评估心电场电位持续时间（FPD）、心率、经Fridericia公式校正的FPD （FPDc）、浓度诱导的FPDc延长10% （FPDc(10)）和心律失常样波形的发生率。结果：用药前设施间绝对值的变异性与设施内FPD、心跳率和FPDc的变异性相似。5种参考药物的FPDc10的设施间变异范围为1.8- 5.8倍。在所有10个设施中，E-4031、莫西沙星和氟氯胺的浓度比其FPDc高1.8- 6.1倍，延长了FPDc并诱导了心律失常样波形（10）。特非那定延长FPDc，诱发心跳骤停，达到FPDc的8.0倍（10）。E-4031、莫西沙星和特非那定的平均FPDc（10）值与报道的导致人类QT间期延长或角扭转的血浆浓度相当。一种I-Ks阻滞剂Chromanol 293B也延长了FPDc，但没有引起心律失常样波形，即使是FPDc的7.4倍（10）。相反，维拉帕米缩短FPDc，阿司匹林不影响FPDc或FP波形。讨论：MEA与hiPS-CMs可以是一种准确预测人类QT间期延长和心律失常倾向的通用方法。(C) 2015爱思唯尔公司版权所有。
Introduction: Drug-induced QT prolongation is a major safety issue during drug development because it may lead to lethal ventricular arrhythmias. In this study, we evaluated the utility of multi-electrode arrays (MEA) with human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) to predict drug-induced QT prolongation and arrhythmia.Methods: Ten facilities evaluated the effects of 7 reference drugs (E-4031, moxifloxacin, flecainide, terfenadine, chromanol 293B, verapamil, and aspirin) using a MED64 MEA system with commercially available hiPS-CMs. Field potential duration (FPD), beat rate, FPD corrected by Fridericia's formula (FPDc), concentration inducing FPDc prolongation by 10% (FPDc(10)), and incidence of arrhythmia-like waveform were evaluated.Results: The inter-facility variability of absolute values before drug application was similar to the intra-facility variability for FPD, beat rate, and FPDc. The inter-facility variability of FPDc10 for 5 reference drugs ranged from 1.8- to 5.8-fold. At all 10 facilities, E-4031, moxifloxacin, and flecainide prolonged FPDc and induced arrhythmia-like waveforms at concentrations 1.8- to 6.1-fold higher than their FPDc(10). Terfenadine prolonged FPDc and induced beating arrest at 8.0 times the FPDc(10). The average FPDc(10) values for E-4031, moxifloxacin, and terfenadine were comparable to reported plasma concentrations that caused QT prolongation or Torsade de Pointes in humans. Chromanol 293B, a I-Ks blocker, also prolonged FPDc but did not induce arrhythmia-like waveforms, even at 7.4 times the FPDc(10). In contrast, verapamil shortened FPDc and aspirin did not affect FPDc or FP waveforms.Discussion: MEA with hiPS-CMs can be a generalizable method for accurately predicting both QT prolongation and arrhythmogenic liability in humans. (C) 2015 Elsevier Inc. All rights reserved.