Recapitulation of Clinical Individual Susceptibility to Drug-Induced QT Prolongation in Healthy Subjects Using iPSC-Derived Cardiomyocytes

• DOI: 10.1016/j.stemcr.2016.12.014
• Publication Date: 2017-01-19T16:08:14Z
• Authors: Tadahiro Shinozawa; Koki Nakamura; Masanobu Shoji; Maya Morita; Maya Kimura; Hatsue Furukawa; Hiroki Ueda; Masanari Shiramoto; Kyoko Matsuguma; Yoshikazu Kaji; Ippei Ikushima; Makoto Yono; Shyh-Yuh Liou; Hirofumi Nagai; Atsushi Nakanishi; Keiji Yamamoto; Seigo Izumo
• Keywords: hERG; Safety pharmacology; Drug Development

To predict drug-induced serious adverse events (SAE) in clinical trials, a model using panel of cells derived from human induced pluripotent stem (hiPSCs) individuals with different susceptibilities could facilitate major advancements translational research terms safety and pharmaco-economics. However, it is unclear whether hiPSC-derived can recapitulate interindividual differences SAE susceptibility populations not having genetic disorders such as healthy subjects. Here, we evaluated individual based on an vitro cardiomyocytes (hiPSC-CMs) pilot study. hiPSCs were generated blood samples ten volunteers to moxifloxacin (Mox)-induced QT prolongation. Different Mox-induced field potential duration (FPD) prolongation values observed the hiPSC-CMs each individual. Interestingly, interval was significantly positively correlated FPD at clinically relevant concentrations (r > 0.66) multiple analyses including concentration-QT analysis. Genomic analysis showed no significant known target-binding sites for Mox other drugs hERG channel subunit, baseline ranges normal. The results suggest that subjects provide proof concept preclinical trials.