Hiroyuki Ando1, Takashi Yoshinaga2, Wataru Yamamoto3, Keiichi Asakura4, Takaaki Uda5, Tomohiko Taniguchi6, Atsuko Ojima6, Raku Shinkyo7, Kiyomi Kikuchi7, Tomoharu Osada8, Seiji Hayashi4, Chieko Kasai9, Norimasa Miyamoto6, Hiroyuki Tashibu10, Daiju Yamazaki11, Atsushi Sugiyama12, Yasunari Kanda11, Kohei Sawada13, Yuko Sekino14. 1. 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. 2. 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. 3. 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. 4. 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. 5. 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. 6. 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. 7. Biopharmaceutical Assessments Core Function Unit, Medicine Development Center, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan. 8. 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. 9. 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. 10. 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. 11. 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. 12. 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. 13. 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. 14. 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.
Abstract
INTRODUCTION: 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%. DISCUSSION: 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.
INTRODUCTION: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%. DISCUSSION: 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: Hua Rong Lu; Haoyu Zeng; Ralf Kettenhofen; Liang Guo; Ivan Kopljar; Karel van Ammel; Fetene Tekle; Ard Teisman; Jin Zhai; Holly Clouse; Jennifer Pierson; Michael Furniss; Armando Lagrutta; Frederick Sannajust; David J Gallacher Journal: Toxicol Sci Date: 2019-08-01 Impact factor: 4.849
Authors: Li Pang; Philip Sager; Xi Yang; Hong Shi; Frederick Sannajust; Mathew Brock; Joseph C Wu; Najah Abi-Gerges; Beverly Lyn-Cook; Brian R Berridge; Norman Stockbridge Journal: Circ Res Date: 2019-10-10 Impact factor: 17.367
Authors: Gary Gintant; Paul Burridge; Lior Gepstein; Sian Harding; Todd Herron; Charles Hong; José Jalife; Joseph C Wu Journal: Circ Res Date: 2019-09-19 Impact factor: 17.367