Center for Devices and Radiological Health, Office of Science and Engineering Laboratories, US Food and Drug Administration, Silver Spring, Maryland, USA.
Center for Drug Evaluation and Research, Office of Clinical Pharmacology, US Food and Drug Administration, Silver Spring, Maryland, USA.
Clin Transl Sci. 2019 Nov;12(6):687-697. doi: 10.1111/cts.12674. Epub 2019 Aug 29.
Induced pluripotent stem cells (iPSCs) have shown promise in investigating donor-specific phenotypes and pathologies. The iPSC-derived cardiomyocytes (iPSC-CMs) could potentially be utilized in personalized cardiotoxicity studies, assessing individual proarrhythmic risk. However, it is unclear how closely iPSC-CMs derived from healthy subjects can recapitulate a range of responses to drugs. It is well known that QT-prolonging drugs induce subject-specific clinical response and that all healthy subjects do not necessarily develop arrhythmias or exhibit similar amounts of QT prolongation. We previously reported this variability in a study of four human ether-a-go-go-related gene (hERG) potassium channel-blocking drugs in which each subject underwent intensive pharmacokinetic and pharmacodynamic sampling such that subjects had 15 time-matched plasma drug concentration and electrocardiogram measurements throughout 24 hours after dosing in a phase I clinical research unit. In this study, iPSC-CMs were generated from those subjects. Their drug-concentration-dependent QT prolongation response from the clinic was compared with in vitro drug-concentration-dependent action potential duration (APD) prolongation response to the same two hERG-blocking drugs, dofetilide and moxifloxacin. Comparative results showed no significant correlation between the subject-specific APD response slopes and clinical QT response slopes to either moxifloxacin (P = 0.75) or dofetilide (P = 0.69). Similarly, no significant correlation was found between baseline QT and baseline APD measurements (P = 0.93). This result advances our current understanding of subject-specific iPSC-CMs and facilitates discussion into factors obscuring correlation and considerations for future studies of subject-specific phenotypes in iPSC-CMs.
诱导多能干细胞（iPSC）在研究供体特异性表型和病理学方面显示出了潜力。iPSC 衍生的心肌细胞（iPSC-CMs）有可能用于个性化的心脏毒性研究，评估个体的致心律失常风险。然而，目前尚不清楚来自健康个体的 iPSC-CMs 能够在多大程度上重现对药物的一系列反应。众所周知，QT 延长药物会引起个体特异性的临床反应，并非所有健康个体都会出现心律失常或表现出相似程度的 QT 延长。我们之前在一项关于四种人 ether-a-go-go 相关基因（hERG）钾通道阻断药物的研究中报告了这种变异性，在该研究中，每个受试者都接受了密集的药代动力学和药效学采样，以便在 I 期临床研究单位中，在给药后 24 小时内，每个受试者都有 15 次时间匹配的血浆药物浓度和心电图测量。在这项研究中，我们从这些受试者中生成了 iPSC-CMs。将他们的药物浓度依赖性 QT 延长反应与体外药物浓度依赖性动作电位持续时间（APD）延长反应进行比较，这两种 hERG 阻断药物是多非利特和莫西沙星。比较结果表明，莫西沙星（P=0.75）或多非利特（P=0.69）的个体 APD 反应斜率与临床 QT 反应斜率之间没有显著相关性。同样，在基线 QT 和基线 APD 测量值之间也没有发现显著相关性（P=0.93）。该结果推进了我们对个体特异性 iPSC-CMs 的现有理解，并促进了对未来 iPSC-CMs 中个体特异性表型相关因素和考虑因素的讨论。
