title: A new paradigm for drug-induced torsadogenic risk assessment using human iPS cell-derived cardiomyocytes.
abstract: BACKGROUND
  Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are anticipated to be a useful tool for conducting proarrhythmia risk assessments of drug candidates. However, a torsadogenic risk prediction paradigm using hiPSC-CMs has not yet been fully established.
  
  
  METHODS
  Extracellular field potentials (FPs) were recorded from hiPSC-CMs using the multi-electrode array (MEA) system. The effects on FPs were evaluated with 60 drugs, including 57 with various clinical torsadogenic risks. Actual drug concentrations in medium were measured using the equilibrium dialysis method with a Rapid Equilibrium Dialysis device. Relative torsade de pointes (TdP) scores were determined for each drug according to the degree of FP duration prolongation and early afterdepolarization occurrence. The margins were calculated from the free concentration in medium and free effective therapeutic plasma concentration. Each drug's results were plotted on a two-dimensional map of relative TdP risk scores versus margins.
  
  
  RESULTS
  Each drug was categorised as high, intermediate, or low risk based on its location within predefined areas of the two-dimensional map. We categorised 19 drugs as high risk; 18 as intermediate risk; and 17 as low risk. We examined the concordance between our categorisation of high and low risk drugs against the torsadogenic risk categorisation in CredibleMeds®. Our system demonstrated high concordance, as reflected in a sensitivity of 81%, specificity of 87%, and accuracy of 83%.
  
  
  CONCLUSIONS
  These results indicate that our torsadogenic risk assessment is reliable and has a potential to replace the hERG assay for torsadogenic risk prediction, however, this system needs to be improved for the accurate of prediction of clinical TdP risk. Here, we propose a novel drug induced torsadogenic risk categorising system using hiPSC-CMs and the MEA system.
authors.affiliation: Japan iPS Cardiac Safety Assessment (JiCSA), 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan(2); Japanese Safety Pharmacology Society (JSPS), 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan(3); Safety Research Laboratories, Ono Pharmaceutical Co., Ltd., 50-10 Yamagishi, Mikuni-cho, Sakai-shi, Fukui 913-8538, Japan. Electronic address: h.andou@ono.co.jp.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Ando
authors.affiliation: Japan iPS Cardiac Safety Assessment (JiCSA), 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan(2); Japanese Safety Pharmacology Society (JSPS), 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan(3); Biopharmaceutical Assessments Core Function Unit, Medicine Development Center, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan. Electronic address: t2-yoshinaga@hhc.eisai.co.jp.
authors.forename: Takashi
authors.initials: T
authors.lastname: Yoshinaga
authors.affiliation: Japan iPS Cardiac Safety Assessment (JiCSA), 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan(2); Pharmaceutical Development Research Laboratories, Toxicology Research Department, Teijin Pharma Limited, 4-3-2 Asahigaoka, Hino-shi, Tokyo 191-8512, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Yamamoto
authors.affiliation: Japan iPS Cardiac Safety Assessment (JiCSA), 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan(2); Japanese Safety Pharmacology Society (JSPS), 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan(3); Discovery Research Labs., Nippon Shinyaku Co., Ltd., 14 Nishinosho-monguchi-cho, Kisshoin, Minami-ku, Kyoto 601-8550, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Asakura
authors.affiliation: Japan iPS Cardiac Safety Assessment (JiCSA), 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan(2); 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: Japan iPS Cardiac Safety Assessment (JiCSA), 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan(2); Biopharmaceutical Assessments Core Function Unit, Medicine Development Center, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan.
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Taniguchi
authors.affiliation: Japan iPS Cardiac Safety Assessment (JiCSA), 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan(2); Biopharmaceutical Assessments Core Function Unit, Medicine Development Center, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan.
authors.forename: Atsuko
authors.initials: A
authors.lastname: Ojima
authors.affiliation: Biopharmaceutical Assessments Core Function Unit, Medicine Development Center, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan.
authors.forename: Raku
authors.initials: R
authors.lastname: Shinkyo
authors.affiliation: Biopharmaceutical Assessments Core Function Unit, Medicine Development Center, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan.
authors.forename: Kiyomi
authors.initials: K
authors.lastname: Kikuchi
authors.affiliation: Japan iPS Cardiac Safety Assessment (JiCSA), 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan(2); Japanese Safety Pharmacology Society (JSPS), 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan(3); Drug Development Service Segment, LSI Medience Corporation, 13-4 Uchikanda 1-chome, Chiyoda-ku, Tokyo 101-8517, Japan.
authors.forename: Tomoharu
authors.initials: T
authors.lastname: Osada
authors.affiliation: Japan iPS Cardiac Safety Assessment (JiCSA), 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan(2); Japanese Safety Pharmacology Society (JSPS), 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan(3); Discovery Research Labs., Nippon Shinyaku Co., Ltd., 14 Nishinosho-monguchi-cho, Kisshoin, Minami-ku, Kyoto 601-8550, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Hayashi
authors.affiliation: Japan iPS Cardiac Safety Assessment (JiCSA), 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan(2); Japanese Safety Pharmacology Society (JSPS), 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan(3); Drug Safety Research Laboratories, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan.
authors.forename: Chieko
authors.initials: C
authors.lastname: Kasai
authors.affiliation: Japan iPS Cardiac Safety Assessment (JiCSA), 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan(2); Biopharmaceutical Assessments Core Function Unit, Medicine Development Center, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan.
authors.forename: Norimasa
authors.initials: N
authors.lastname: Miyamoto
authors.affiliation: Japan iPS Cardiac Safety Assessment (JiCSA), 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan(2); Japanese Safety Pharmacology Society (JSPS), 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan(3); Research Administration Department, Ina Research Inc., 2148-188 Nishiminowa, Ina-shi, Nagano 399-4501, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tashibu
authors.affiliation: Japan iPS Cardiac Safety Assessment (JiCSA), 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan(2); Division of Pharmacology, National Institute of Health Sciences (NIHS), 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan.
authors.forename: Daiju
authors.initials: D
authors.lastname: Yamazaki
authors.affiliation: Japan iPS Cardiac Safety Assessment (JiCSA), 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan(2); Japanese Safety Pharmacology Society (JSPS), 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan(3); Department of Pharmacology, Faculty of Medicine, Toho University, 5-21-16 Omori-nishi, Ota-ku, Tokyo 143-8540, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Sugiyama
authors.affiliation: Japan iPS Cardiac Safety Assessment (JiCSA), 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan(2); Division of Pharmacology, National Institute of Health Sciences (NIHS), 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan.
authors.forename: Yasunari
authors.initials: Y
authors.lastname: Kanda
authors.affiliation: Japan iPS Cardiac Safety Assessment (JiCSA), 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan(2); Japanese Safety Pharmacology Society (JSPS), 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan(3); Biopharmaceutical Assessments Core Function Unit, Medicine Development Center, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Sawada
authors.affiliation: Japan iPS Cardiac Safety Assessment (JiCSA), 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan(2); Japanese Safety Pharmacology Society (JSPS), 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan(3); Division of Pharmacology, National Institute of Health Sciences (NIHS), 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Sekino
mesh_terms: D000200:Action Potentials / Q000187:drug effects* / Q000502:physiology; D054715:Cardiotoxins / Q000633:toxicity*; D002478:Cells, Cultured; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects* / Q000502:physiology; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000502:physiology; D018570:Risk Assessment; D016171:Torsades de Pointes / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology
chemical_list: D054715:Cardiotoxins
keywords: Concordance; Early afterdepolarization; Field potential duration; Free concentration; Human induced pluripotent stem cell-derived cardiomyocytes; Multi-electrode array; Proarrhythmia; Risk categorisation; Torsade de pointes; Torsadogenic risk