title: CSAHi study: Validation of multi-electrode array systems (MEA60/2100) for prediction of drug-induced proarrhythmia using human iPS cell-derived cardiomyocytes -assessment of inter-facility and cells lot-to-lot-variability.
abstract: In vitro screening of hERG channels are recommended under ICH S7B guidelines to predict drug-induced QT prolongation and Torsade de Pointes (TdP), whereas proarrhythmia is known to be evoked by blockage of other ion channels involved in cardiac contraction and compensation mechanisms. A consortium for drug safety assessment using human iPS cells-derived cardiomyocytes (hiPS-CMs), CSAHi, has been organized to establish a novel in vitro test system that would enable better prediction of drug-induced proarrhythmia and QT prolongation. Here we report the inter-facility and cells lot-to-lot variability evaluated with FPDc (corrected field potential duration), FPDc10 (10% FPDc change concentration), beat rate and incidence of arrhythmia-like waveform or arrest on hiPS-CMs in a multi-electrode array system. Arrhythmia-like waveforms were evident for all test compounds, other than chromanol 293B, that evoked FPDc prolongation in this system and are reported to induce TdP in clinical practice. There was no apparent cells lot-to-lot variability, while inter-facility variabilities were limited within ranges from 3.9- to 20-folds for FPDc10 and about 10-folds for the minimum concentration inducing arrhythmia-like waveform or arrests. In conclusion, the new assay model reported here would enable accurate prediction of a drug potential for proarrhythmia.
authors.affiliation: Preclinical Research Laboratories, Sumitomo Dainippon Pharma Co., Ltd., 3-1-98 Kasugade-naka, Konohana-ku, Osaka 554-0022, Japan.
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Nozaki
authors.affiliation: Preclinical Research Laboratories, Sumitomo Dainippon Pharma Co., Ltd., 3-1-98 Kasugade-naka, Konohana-ku, Osaka 554-0022, Japan.
authors.forename: Yayoi
authors.initials: Y
authors.lastname: Honda
authors.affiliation: Preclinical Research Laboratories, Sumitomo Dainippon Pharma Co., Ltd., 3-1-98 Kasugade-naka, Konohana-ku, Osaka 554-0022, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Watanabe
authors.affiliation: Research Laboratory for Development, Shionogi & Co., Ltd., 3-1-1, Futaba-cho, Toyonaka, Osaka 561-0825, Japan; Consortium for Safety Assessment Using Human iPS Cells (CSAHi), Japan.
authors.forename: Shota
authors.initials: S
authors.lastname: Saiki
authors.affiliation: Research Laboratory for Development, Shionogi & Co., Ltd., 3-1-1, Futaba-cho, Toyonaka, Osaka 561-0825, Japan.
authors.forename: Kiyotaka
authors.initials: K
authors.lastname: Koyabu
authors.affiliation: Research Laboratory for Development, Shionogi & Co., Ltd., 3-1-1, Futaba-cho, Toyonaka, Osaka 561-0825, Japan.
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Itoh
authors.affiliation: Research Center, Taisho Pharmaceutical Co., Ltd., 1-403, Yoshino-cho, Kita-ku, Saitama-shi, Saitama 331-9530, Japan; Consortium for Safety Assessment Using Human iPS Cells (CSAHi), Japan.
authors.forename: Chiho
authors.initials: C
authors.lastname: Nagasawa
authors.affiliation: Research Center, Taisho Pharmaceutical Co., Ltd., 1-403, Yoshino-cho, Kita-ku, Saitama-shi, Saitama 331-9530, Japan.
authors.forename: Chiaki
authors.initials: C
authors.lastname: Nakamori
authors.affiliation: Research Center, Taisho Pharmaceutical Co., Ltd., 1-403, Yoshino-cho, Kita-ku, Saitama-shi, Saitama 331-9530, Japan.
authors.forename: Chiaki
authors.initials: C
authors.lastname: Nakayama
authors.affiliation: Research Center, Taisho Pharmaceutical Co., Ltd., 1-403, Yoshino-cho, Kita-ku, Saitama-shi, Saitama 331-9530, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Iwasaki
authors.affiliation: Nippon Boehringer Ingelheim Co., Ltd., 6-7-5, Minatojima-Minamimachi, Chuo-ku, Kobe, Hyogo, 650-0047, Japan; Consortium for Safety Assessment Using Human iPS Cells (CSAHi), Japan.
authors.forename: Shinobu
authors.initials: S
authors.lastname: Suzuki
authors.affiliation: 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: Research Laboratories, Toyama Chemical Co., Ltd., 4-1, Shimookui 2-chome, Toyama 930-8508, Japan; Consortium for Safety Assessment Using Human iPS Cells (CSAHi), Japan.
authors.forename: Etsushi
authors.initials: E
authors.lastname: Takahashi
authors.affiliation: Research Laboratories, Toyama Chemical Co., Ltd., 4-1, Shimookui 2-chome, Toyama 930-8508, Japan.
authors.forename: Kaori
authors.initials: K
authors.lastname: Miyamoto
authors.affiliation: Toxicology Research Laboratory, Kyorin Pharmaceutical Co., Ltd., 1848, Nogi, Nogi-machi, Shimotsuga-gun, Tochigi, 329-0114, Japan; Consortium for Safety Assessment Using Human iPS Cells (CSAHi), Japan.
authors.forename: Atsuhiro
authors.initials: A
authors.lastname: Yamanishi
authors.affiliation: Toxicology Research Laboratory, Kyorin Pharmaceutical Co., Ltd., 1848, Nogi, Nogi-machi, Shimotsuga-gun, Tochigi, 329-0114, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Endo
authors.affiliation: Toxicology Research Laboratory, Kyorin Pharmaceutical Co., Ltd., 1848, Nogi, Nogi-machi, Shimotsuga-gun, Tochigi, 329-0114, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Shinozaki
authors.affiliation: Toxicology Research Laboratory, Kyorin Pharmaceutical Co., Ltd., 1848, Nogi, Nogi-machi, Shimotsuga-gun, Tochigi, 329-0114, Japan.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Nogawa
authors.affiliation: Preclinical Research Laboratories, Sumitomo Dainippon Pharma Co., Ltd., 3-1-98 Kasugade-naka, Konohana-ku, Osaka 554-0022, Japan; Consortium for Safety Assessment Using Human iPS Cells (CSAHi), Japan; Non-Clinical Evaluation Expert Committee, Drug Evaluation Committee, Japan Pharmaceutical Manufacturers Association (JPMA), 2-3-11 Nihonbashi-Honcho, Chuo-ku, Tokyo 103-0023, Japan. Electronic address: takeshi-kunimatsu@ds-pharma.co.jp.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kunimatsu
mesh_terms: D000200:Action Potentials; D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D001681:Biological Assay; D066126:Cardiotoxicity; D018929:Cell Culture Techniques; D002454:Cell Differentiation; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D000072237:ERG1 Potassium Channel / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004867:Equipment Design; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects* / Q000378:metabolism; D007564:Japan; D008839:Microelectrodes; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D019370:Observation; D026902:Potassium Channel Blockers / Q000633:toxicity*; D015203:Reproducibility of Results; D018570:Risk Assessment; D018675:Toxicity Tests / Q000295:instrumentation* / Q000379:methods / Q000592:standards
chemical_list: D000072237:ERG1 Potassium Channel; C000606913:KCNH2 protein, human; D026902:Potassium Channel Blockers
keywords: Comprehensive in vitro Proarrthythmia assay (CiPA); Consortium for drug safety assessment using human iPS cells (CSAHi); Early after depolarization (EAD) or triggered activity (TA); Human iPS cells-derived cardiomyocytes (hiPS-CMs); Inter-facility variability; Multi electrode array (MEA)