Takashi Kitaguchi1, Yuta Moriyama2, Tomohiko Taniguchi3, Atsuko Ojima3, Hiroyuki Ando4, Takaaki Uda4, Koji Otabe5, Masao Oguchi5, Shigekazu Shimizu6, Hiroyuki Saito6, Maya Morita7, Atsushi Toratani8, Mahoko Asayama8, Wataru Yamamoto9, Emi Matsumoto9, Daisuke Saji10, Hiroki Ohnaka10, Kohji Tanaka11, Ikumi Washio11, Norimasa Miyamoto12. 1. Non-Clinical Evaluation Expert Committee, Drug Evaluation Committee, Japan Pharmaceutical Manufacturers Association (JPMA), 2-3-11 Nihonbashi-Honcho, Chuo-ku, Tokyo 103-0023, Japan; Consortium for Safety Assessment using Human iPS Cells (CSAHi), Japan; Discovery Research, Mochida Pharmaceutical Co., Ltd., 722, Uenohara, Jimba, Gotemba, Shizuoka 412-8524, Japan. Electronic address: takashi.kitaguchi@mochida.co.jp. 2. Consortium for Safety Assessment using Human iPS Cells (CSAHi), Japan; Discovery Research, Mochida Pharmaceutical Co., Ltd., 722, Uenohara, Jimba, Gotemba, Shizuoka 412-8524, Japan. 3. Consortium for Safety Assessment using Human iPS Cells (CSAHi), Japan; Biopharmaceutical Assessments Core Function Unit, Eisai Product Creation Systems, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan. 4. Consortium for Safety Assessment using Human iPS Cells (CSAHi), Japan; Safety Research Laboratories, Ono Pharmaceutical Co., Ltd., 50-10, Yamagishi, Mikuni-cho, Sakai-shi, Fukui 913-8538, Japan. 5. Consortium for Safety Assessment using Human iPS Cells (CSAHi), Japan; Research Administration Department, Ina Research Inc., 2148-188, Nishiminowa, Ina-shi, Nagano 399-4501, Japan. 6. Consortium for Safety Assessment using Human iPS Cells (CSAHi), Japan; CMIC Bioresearch Center Co., Ltd., 10221, Kobuchisawa-cho, Hokuto-shi, Yamanashi 408-0044, Japan. 7. Consortium for Safety Assessment using Human iPS Cells (CSAHi), Japan; Drug Safety Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd., 26-1, Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. 8. Consortium for Safety Assessment using Human iPS Cells (CSAHi), Japan; Research Division, Mitsubishi Tanabe Pharma Corporation, 1-1-1, Kazusakamatari, Kisarazu, Chiba 292-0818, Japan. 9. Consortium for Safety Assessment using Human iPS Cells (CSAHi), Japan; Pharmaceutical Development Research Laboratories, Toxicology Research Department, Teijin Pharma Ltd., 4-3-2, Asahigaoka, Hino-shi, Tokyo 191-8512, Japan. 10. Consortium for Safety Assessment using Human iPS Cells (CSAHi), Japan; Shiga Laboratory, Nisseibilis Co., Ltd., 555, Ukawa, Minakuchi-cho, Koka, Shiga 528-0052, Japan. 11. Consortium for Safety Assessment using Human iPS Cells (CSAHi), Japan; Kobe Pharma Research Institute, Nippon Boehringer Ingelheim Co., Ltd., 6-7-5, Minatojima-Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan. 12. Non-Clinical Evaluation Expert Committee, Drug Evaluation Committee, Japan Pharmaceutical Manufacturers Association (JPMA), 2-3-11 Nihonbashi-Honcho, Chuo-ku, Tokyo 103-0023, Japan; Consortium for Safety Assessment using Human iPS Cells (CSAHi), Japan; Biopharmaceutical Assessments Core Function Unit, Eisai Product Creation Systems, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan.
Abstract
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% (FPDc10), 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 FPDc10. Terfenadine prolonged FPDc and induced beating arrest at 8.0 times the FPDc10. The average FPDc10 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 IKs blocker, also prolonged FPDc but did not induce arrhythmia-like waveforms, even at 7.4 times the FPDc10. 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.
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% (FPDc10), 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 FPDc10. Terfenadine prolonged FPDc and induced beating arrest at 8.0 times the FPDc10. The average FPDc10 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 IKs blocker, also prolonged FPDc but did not induce arrhythmia-like waveforms, even at 7.4 times the FPDc10. 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.
Authors: Paramdeep S Dhillon; Giulia Domenichini; Hanney Gonna; Anthony Li; Nadia Sunni; Michael Mahmoudi; Mark M Gallagher Journal: J Med Case Rep Date: 2016-09-15
Authors: Matthew T McPheeters; Yves T Wang; Andreas A Werdich; Michael W Jenkins; Kenneth R Laurita Journal: PLoS One Date: 2017-08-24 Impact factor: 3.240