Takashi Kitaguchi1, Yuta Moriyama2, Tomohiko Taniguchi3, Sanae Maeda3, Hiroyuki Ando4, Takaaki Uda4, Koji Otabe5, Masao Oguchi5, Shigekazu Shimizu6, Hiroyuki Saito6, Atsushi Toratani7, Mahoko Asayama7, Wataru Yamamoto8, Emi Matsumoto8, Daisuke Saji9, Hiroki Ohnaka9, Norimasa Miyamoto10. 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(1); 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(1); 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(1); Biopharmaceutical Assessment Core Function Unit, Medicine Development Center, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan. 4. Consortium for Safety Assessment using Human iPS Cells (CSAHi), Japan(1); 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(1); 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(1); Bioresearch Center, CMIC Pharma Science Co., Ltd., 10221, Kobuchisawa-cho, Hokuto-shi, Yamanashi 408-0044, Japan. 7. Consortium for Safety Assessment using Human iPS Cells (CSAHi), Japan(1); Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 2-2-50, Kawagishi, Toda, Saitama 335-8505, Japan. 8. Consortium for Safety Assessment using Human iPS Cells (CSAHi), Japan(1); Pharmaceutical Development Research Laboratories, Toxicology Research Department, Teijin Pharma Ltd., 4-3-2, Asahigaoka, Hino-shi, Tokyo 191-8512, Japan. 9. Consortium for Safety Assessment using Human iPS Cells (CSAHi), Japan(1); Shiga Laboratory, Nisseibilis Co., Ltd., 555, Ukawa, Minakuchi-cho, Koka, Shiga 528-0052, Japan. 10. 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(1); Biopharmaceutical Assessment Core Function Unit, Medicine Development Center, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan.
Abstract
INTRODUCTION: The use of multi-electrode arrays (MEA) in combination with human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) provides a promising method to predict comprehensive cardiotoxicity, including drug-induced QT prolongation and arrhythmia. We previously demonstrated that MEA in combination with hiPSC-CMs could provide a generalizable platform by using 7 reference drugs at 10 testing facilities. Using this approach, we evaluated responses to reference drugs that modulate a range of cardiac ion currents and have a range of arrhythmogenic effects. METHODS: We used the MEA system (MED64) and commercially available hiPSC-CMs (iCell cardiomyocytes) to evaluate drug effects on the beat rate, field potential duration (FPD), FPD corrected by Fridericia's formula (FPDc), and the incidence of arrhythmia-like waveforms. RESULTS: This assay detected the repolarization effects of Bay K8644, mibefradil, NS1643, levcromakalim, and ouabain; and the chronotropic effects of isoproterenol, ZD7288, and BaCl2. Chronotropy was also affected by K+ and Ca2+ current modulation. This system detected repolarization delays and the arrhythmogenic effects of quinidine, cisapride, thioridazine, astemizole, bepridil, and pimozide more sensitively than the established guinea pig papillary muscle action potential assay. It also predicted clinical QT prolongation by drugs with multiple ion channel effects (fluoxetine, amiodarone, tolterodine, vanoxerine, alfuzosin, and ranolazine). DISCUSSION: MEA in combination with hiPSC-CMs may provide a powerful method to detect various cardiac electrophysiological effects, QT prolongation, and arrhythmia during drug discovery. However, the data require careful interpretation to predict chronotropic effects and arrhythmogenic effects of candidate drugs with multiple ion channel effects.
INTRODUCTION: The use of multi-electrode arrays (MEA) in combination with human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) provides a promising method to predict comprehensive cardiotoxicity, including drug-induced QT prolongation and arrhythmia. We previously demonstrated that MEA in combination with hiPSC-CMs could provide a generalizable platform by using 7 reference drugs at 10 testing facilities. Using this approach, we evaluated responses to reference drugs that modulate a range of cardiac ion currents and have a range of arrhythmogenic effects. METHODS: We used the MEA system (MED64) and commercially available hiPSC-CMs (iCell cardiomyocytes) to evaluate drug effects on the beat rate, field potential duration (FPD), FPD corrected by Fridericia's formula (FPDc), and the incidence of arrhythmia-like waveforms. RESULTS: This assay detected the repolarization effects of Bay K8644, mibefradil, NS1643, levcromakalim, and ouabain; and the chronotropic effects of isoproterenol, ZD7288, and BaCl2. Chronotropy was also affected by K+ and Ca2+ current modulation. This system detected repolarization delays and the arrhythmogenic effects of quinidine, cisapride, thioridazine, astemizole, bepridil, and pimozide more sensitively than the established guinea pig papillary muscle action potential assay. It also predicted clinical QT prolongation by drugs with multiple ion channel effects (fluoxetine, amiodarone, tolterodine, vanoxerine, alfuzosin, and ranolazine). DISCUSSION: MEA in combination with hiPSC-CMs may provide a powerful method to detect various cardiac electrophysiological effects, QT prolongation, and arrhythmia during drug discovery. However, the data require careful interpretation to predict chronotropic effects and arrhythmogenic effects of candidate drugs with multiple ion channel effects.
Authors: Alec S T Smith; Eunpyo Choi; Kevin Gray; Jesse Macadangdang; Eun Hyun Ahn; Elisa C Clark; Michael A Laflamme; Joseph C Wu; Charles E Murry; Leslie Tung; Deok-Ho Kim Journal: Nano Lett Date: 2019-12-23 Impact factor: 11.189