title: 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.
abstract: BACKGROUND
  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.
  
  
  CONCLUSIONS
  MEA with hiPS-CMs can be a generalizable method for accurately predicting both QT prolongation and arrhythmogenic liability in humans.
authors.affiliation: 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.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kitaguchi
authors.affiliation: Consortium for Safety Assessment using Human iPS Cells (CSAHi), Japan; Discovery Research, Mochida Pharmaceutical Co., Ltd., 722, Uenohara, Jimba, Gotemba, Shizuoka 412-8524, Japan.
authors.forename: Yuta
authors.initials: Y
authors.lastname: Moriyama
authors.affiliation: 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.
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Taniguchi
authors.affiliation: 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.
authors.forename: Atsuko
authors.initials: A
authors.lastname: Ojima
authors.affiliation: 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.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Ando
authors.affiliation: 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.
authors.forename: Takaaki
authors.initials: T
authors.lastname: Uda
authors.affiliation: 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.
authors.forename: Koji
authors.initials: K
authors.lastname: Otabe
authors.affiliation: 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.
authors.forename: Masao
authors.initials: M
authors.lastname: Oguchi
authors.affiliation: Consortium for Safety Assessment using Human iPS Cells (CSAHi), Japan; CMIC Bioresearch Center Co., Ltd., 10221, Kobuchisawa-cho, Hokuto-shi, Yamanashi 408-0044, Japan.
authors.forename: Shigekazu
authors.initials: S
authors.lastname: Shimizu
authors.affiliation: Consortium for Safety Assessment using Human iPS Cells (CSAHi), Japan; CMIC Bioresearch Center Co., Ltd., 10221, Kobuchisawa-cho, Hokuto-shi, Yamanashi 408-0044, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Saito
authors.affiliation: 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.
authors.forename: Maya
authors.initials: M
authors.lastname: Morita
authors.affiliation: 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.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Toratani
authors.affiliation: 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.
authors.forename: Mahoko
authors.initials: M
authors.lastname: Asayama
authors.affiliation: 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.
authors.forename: Wataru
authors.initials: W
authors.lastname: Yamamoto
authors.affiliation: 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.
authors.forename: Emi
authors.initials: E
authors.lastname: Matsumoto
authors.affiliation: Consortium for Safety Assessment using Human iPS Cells (CSAHi), Japan; Shiga Laboratory, Nisseibilis Co., Ltd., 555, Ukawa, Minakuchi-cho, Koka, Shiga 528-0052, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Saji
authors.affiliation: Consortium for Safety Assessment using Human iPS Cells (CSAHi), Japan; Shiga Laboratory, Nisseibilis Co., Ltd., 555, Ukawa, Minakuchi-cho, Koka, Shiga 528-0052, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Ohnaka
authors.affiliation: 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.
authors.forename: Kohji
authors.initials: K
authors.lastname: Tanaka
authors.affiliation: 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.
authors.forename: Ikumi
authors.initials: I
authors.lastname: Washio
authors.affiliation: 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.
authors.forename: Norimasa
authors.initials: N
authors.lastname: Miyamoto
mesh_terms: D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000175:diagnosis; D018929:Cell Culture Techniques / Q000379:methods*; D003226:Congresses as Topic; D015925:Cryopreservation / Q000379:methods; D064420:Drug-Related Side Effects and Adverse Reactions / Q000175:diagnosis; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects* / Q000502:physiology; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000175:diagnosis; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000502:physiology; D004364:Pharmaceutical Preparations / Q000008:administration & dosage; D011237:Predictive Value of Tests
chemical_list: D004364:Pharmaceutical Preparations
keywords: CSAHi; Field potential; Human induced pluripotent stem cell-derived cardiomyocytes; Multi-electrode array; Proarrhythmia; QT prolongation; Torsade de pointes