| Affiliation: | 1. Japan iPS Cardiac Safety Assessment (JiCSA), Japan;2. Division of Pharmacology, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki-ku, Kawasaki, Kanagawa 210-9501, Japan;3. Consortium for Safety Assessment Using Human iPS Cells (CSAHi), Japan;4. Mochida Pharmaceutical Co. Ltd., 722 Uenohara, Jimba, Gotemba, Shizuoka 412-8524, Japan;5. Kaken Pharmaceutical Co. Ltd., 14 Minamikawahara-cho, Shinomiya, Yamashina-ku, Kyoto, 607-8042, Japan;6. Eisai Co. Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan;g. Kyorin Pharmaceutical Co. Ltd., 1848 Nogi, Nogimachi, Shimotsugagun, Tochigi 329-0114, Japan;h. NISSEI BILIS Co. Ltd., 555 Ukawa, Minakuchi-cho, Koka, Shiga 528-0052, Japan;i. Toyama Chemical Co. Ltd., 2-4-1 Shimookui, Toyama, Toyama 930-8508, Japan;j. Ina Research Inc., 2148-188 Nishiminowa, Ina-shi, Nagano 399-4501, Japan;k. Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan |
| Abstract: | ![]()
Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are expected to become a useful tool for proarrhythmia risk prediction in the non-clinical drug development phase. Several features including electrophysiological properties, ion channel expression profile and drug responses were investigated using commercially available hiPSC-CMs, such as iCell-CMs and Cor.4U-CMs. Although drug-induced arrhythmia has been extensively examined by microelectrode array (MEA) assays in iCell-CMs, it has not been fully understood an availability of Cor.4U-CMs for proarrhythmia risk. Here, we evaluated the predictivity of proarrhythmia risk using Cor.4U-CMs. MEA assay revealed linear regression between inter-spike interval and field potential duration (FPD). The hERG inhibitor E?4031 induced reverse-use dependent FPD prolongation. We next evaluated the proarrhythmia risk prediction by a two-dimensional map, which we have previously proposed. We determined the relative torsade de pointes risk score, based on the extent of FPD with Fridericia's correction (FPDcF) change and early afterdepolarization occurrence, and calculated the margins normalized to free effective therapeutic plasma concentrations. The drugs were classified into three risk groups using the two-dimensional map. This risk-categorization system showed high concordance with the torsadogenic information obtained by a public database CredibleMeds. Taken together, these results indicate that Cor.4U-CMs can be used for drug-induced proarrhythmia risk prediction. |
