Shinozawa Tadahiro, Nakamura Koki, Shoji Masanobu, Morita Maya, Kimura Maya, Furukawa Hatsue, Ueda Hiroki, Shiramoto Masanari, Matsuguma Kyoko, Kaji Yoshikazu, Ikushima Ippei, Yono Makoto, Liou Shyh-Yuh, Nagai Hirofumi, Nakanishi Atsushi, Yamamoto Keiji, Izumo Seigo
Drug Safety Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1 Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
Global Medical Affairs-Japan, Takeda Pharmaceutical Company Limited, 12-10 Nihonbashi 2-chome, Chuo-ku, Tokyo 103-8668, Japan.
Stem Cell Reports. 2017 Feb 14;8(2):226-234. doi: 10.1016/j.stemcr.2016.12.014. Epub 2017 Jan 19.
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.
为了在临床试验中预测药物引起的严重不良事件（SAE），使用来自具有不同易感性个体的人诱导多能干细胞（hiPSC）衍生的细胞系构建的模型，在安全性和药物经济学方面可能推动转化研究取得重大进展。然而，尚不清楚hiPSC衍生的细胞是否能够重现无遗传疾病人群（如健康受试者）在药物诱导的SAE易感性方面的个体差异。在此，我们基于使用hiPSC衍生的心肌细胞（hiPSC-CM）的体外模型评估了SAE易感性的个体差异，作为一项初步研究。从十名对莫西沙星（Mox）诱导的QT延长具有不同易感性的健康志愿者的血液样本中生成hiPSC。在来自每个个体的hiPSC-CM中观察到不同的Mox诱导的场电位持续时间（FPD）延长值。有趣的是，在包括浓度-QT分析在内的多项分析中，在临床相关浓度下QT间期与FPD呈显著正相关（r>0.66）。基因组分析显示，在Mox和其他药物（如hERG通道亚基）的已知靶点结合位点上，个体间无显著差异，且基线QT范围正常。结果表明，来自健康受试者的hiPSC-CM重现了对Mox诱导的QT延长的易感性，并为体外临床前试验提供了概念验证。
