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

被引：62

作者：

Kitaguchi, Takashi ^{[1
,2
,3
]}

Moriyama, Yuta ^{[2
,3
]}

Taniguchi, Tomohiko ^{[2
,4
]}

Ojima, Atsuko ^{[2
,4
]}

Ando, Hiroyuki ^{[2
,5
]}

Uda, Takaaki ^{[2
,5
]}

Otabe, Koji ^{[2
,6
]}

Oguchi, Masao ^{[2
,6
]}

Shimizu, Shigekazu ^{[2
,7
]}

Saito, Hiroyuki ^{[2
,7
]}

Morita, Maya ^{[2
,8
]}

Toratani, Atsushi ^{[2
,9
]}

Asayama, Mahoko ^{[2
,9
]}

Yamamoto, Wataru ^{[2
,10
]}

Matsumoto, Emi ^{[2
,10
]}

Saji, Daisuke ^{[2
,11
]}

Ohnaka, Hiroki ^{[2
,11
]}

Tanaka, Kohji ^{[2
,12
]}

Washio, Ikumi ^{[2
,12
]}

Miyamoto, Norimasa ^{[1
,2
,4
]}

机构：

[1] Japan Pharmaceut Mfg Assoc, Drug Evaluat Comm, Nonclin Evaluat Expert Comm, Chuo Ku, 2-3-11 Nihonbashi Honcho, Tokyo 1030023, Japan

[2] Consortium Safety Assessment Using Human iPS Cell, Tokyo, Japan

[3] Mochida Pharmaceut Co Ltd, Discovery Res, 722 Uenohara, Gotemba, Shizuoka 4128524, Japan

[4] Eisai & Co Ltd, Eisai Prod Creat Syst, Biopharmaceut Assessments Core Funct Unit, 5-1-3 Tokodai, Tsukuba, Ibaraki 3002635, Japan

[5] Ono Pharmaceut Co Ltd, Safety Res Labs, 50-10,Yamagishi,Mikuni Cho, Sakai, Fukui 9138538, Japan

[6] Ina Res Inc, Res Adm Dept, 2148-188 Nishiminowa, Ina, Nagano 3994501, Japan

[7] CMIC Biores Ctr Co Ltd, 10221 Kobuchisawa Cho, Hokuto, Yamanashi 4080044, Japan

[8] Takeda Pharmaceut Co Ltd, Div Pharmaceut Res, Drug Safety Res Labs, 26-1,Muraoka Higashi 2 Chome, Fujisawa, Kanagawa 2518555, Japan

[9] Mitsubishi Tanabe Pharma Corp, Div Res, 1-1-1 Kazusakamatari, Chiba 2920818, Japan

[10] Teijin Pharma Ltd, Toxicol Res Dept, Pharmaceut Dev Res Labs, 4-3-2 Asahigaoka, Hino, Tokyo 1918512, Japan

[11] Nisseibilis Co Ltd, Shiga Lab, 555 Ukawa,Minakuchi Cho, Koka, Shiga 5280052, Japan

[12] Nippon Boehringer Ingelheim Co Ltd, Kobe Pharma Res Inst, Chuo Ku, 6-7-5 Minatojima Minamimachi, Kobe, Hyogo 6500047, Japan

来源：

JOURNAL OF PHARMACOLOGICAL AND TOXICOLOGICAL METHODS | 2016年 / 78卷

关键词：

CSAHi; Field potential; Human induced pluripotent stem cell-derived cardiomyocytes; Multi-electrode array; Proarrhythmia; QT prolongation; Torsade de pointes; INTERVAL PROLONGATION; CARDIAC SAFETY; IN-VITRO; DE-POINTES; MODELS; REPOLARIZATION; PHARMACOLOGY; TERFENADINE; PRODACT; DELAY;

D O I：

10.1016/j.vascn.2015.12.002

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

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.

引用

页码：93 / 102

页数：10

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