title: Recapitulation of Clinical Individual Susceptibility to Drug-Induced QT Prolongation in Healthy Subjects Using iPSC-Derived Cardiomyocytes.
abstract: To predict drug-induced serious adverse events (SAE) in clinical trials, a model using a panel of cells derived from human induced pluripotent stem cells (hiPSCs) of individuals with different susceptibilities could facilitate major advancements in translational research in terms of safety and pharmaco-economics. However, it is unclear whether hiPSC-derived cells can recapitulate interindividual differences in drug-induced SAE susceptibility in populations not having genetic disorders such as healthy subjects. Here, we evaluated individual differences in SAE susceptibility based on an in vitro model using hiPSC-derived cardiomyocytes (hiPSC-CMs) as a pilot study. hiPSCs were generated from blood samples of ten healthy volunteers with different susceptibilities to moxifloxacin (Mox)-induced QT prolongation. Different Mox-induced field potential duration (FPD) prolongation values were observed in the hiPSC-CMs from each individual. Interestingly, the QT interval was significantly positively correlated with FPD at clinically relevant concentrations (r > 0.66) in multiple analyses including concentration-QT analysis. Genomic analysis showed no interindividual significant differences in known target-binding sites for Mox and other drugs such as the hERG channel subunit, and baseline QT ranges were normal. The results suggest that hiPSC-CMs from healthy subjects recapitulate susceptibility to Mox-induced QT prolongation and provide proof of concept for in vitro preclinical trials.
authors.affiliation: Drug Safety Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1 Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: tadahiro.shinozawa@takeda.com.
authors.forename: Tadahiro
authors.initials: T
authors.lastname: Shinozawa
authors.affiliation: Global Medical Affairs-Japan, Takeda Pharmaceutical Company Limited, 12-10 Nihonbashi 2-chome, Chuo-ku, Tokyo 103-8668, Japan.
authors.forename: Koki
authors.initials: K
authors.lastname: Nakamura
authors.affiliation: Integrated Technology Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1 Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Masanobu
authors.initials: M
authors.lastname: Shoji
authors.affiliation: Drug Safety Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1 Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Maya
authors.initials: M
authors.lastname: Morita
authors.affiliation: Drug Safety Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1 Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Maya
authors.initials: M
authors.lastname: Kimura
authors.affiliation: Drug Safety Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1 Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Hatsue
authors.initials: H
authors.lastname: Furukawa
authors.affiliation: Development Operations Department, Takeda Development Center Japan, Pharmaceutical Development Division, Takeda Pharmaceutical Company Limited, 12-10 Nihonbashi 2-chome, Chuo-ku, Tokyo 103-8668, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Ueda
authors.affiliation: Hakata Clinic, Souseikai, 6-18 Tenya-machi, Hakata-ku, Fukuoka 812-0025, Japan.
authors.forename: Masanari
authors.initials: M
authors.lastname: Shiramoto
authors.affiliation: Sugioka Memorial Hospital (current Fukuoka Mirai Hospital), Souseikai, 5-1 Kashii-Teriha 3-chome, Higashi-ku, Fukuoka 813-0017, Japan.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Matsuguma
authors.affiliation: Sumida Hospital, Souseikai, 1-29-1 Honjo, Sumida-ku, Tokyo 130-0004, Japan.
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Kaji
authors.affiliation: Sumida Hospital, Souseikai, 1-29-1 Honjo, Sumida-ku, Tokyo 130-0004, Japan.
authors.forename: Ippei
authors.initials: I
authors.lastname: Ikushima
authors.affiliation: Nishi-Kumamoto Hospital, Souseikai, 1012 Koga, Tomiai-machi, Minami-ku, Kumamoto 861-4157, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Yono
authors.affiliation: Development Operations Department, Takeda Development Center Japan, Pharmaceutical Development Division, Takeda Pharmaceutical Company Limited, 12-10 Nihonbashi 2-chome, Chuo-ku, Tokyo 103-8668, Japan.
authors.forename: Shyh-Yuh
authors.initials: SY
authors.lastname: Liou
authors.affiliation: Drug Safety Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1 Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Nagai
authors.affiliation: Integrated Technology Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1 Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nakanishi
authors.affiliation: Integrated Technology Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1 Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Keiji
authors.initials: K
authors.lastname: Yamamoto
authors.affiliation: Regenerative Medicine Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1 Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Seigo
authors.initials: S
authors.lastname: Izumo
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000483:Alleles; D002454:Cell Differentiation; D000072237:ERG1 Potassium Channel / Q000235:genetics / Q000378:metabolism; D004562:Electrocardiography; D055724:Electrophysiological Phenomena / Q000187:drug effects*; D020869:Gene Expression Profiling; D005787:Gene Frequency; D064368:Healthy Volunteers; D006329:Heart Conduction System / Q000187:drug effects; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology*; D008297:Male; D009154:Mutation; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*; D020641:Polymorphism, Single Nucleotide
chemical_list: D000072237:ERG1 Potassium Channel; C000606913:KCNH2 protein, human
keywords: QT prolongation; cardiomyocytes; clinical trial; drug safety assessment; drug susceptibility; iPSC; inter-individual difference