Division of Pharmacology, National Institute of Health Sciences (NIHS).
Division of Pharmaceutical Sciences, Graduated School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University.
J Toxicol Sci. 2021;46(8):359-369. doi: 10.2131/jts.46.359.
Predicting drug-induced side effects in the cardiovascular system is very important because it can lead to the discontinuation of new drugs/candidates or the withdrawal of marketed drugs. Although chronic assessment of cardiac contractility is an important issue in safety pharmacology, an in vitro evaluation system has not been fully developed. We previously developed an imaging-based contractility assay system to detect acute cardiotoxicity using human iPS cell-derived cardiomyocytes (hiPSC-CMs). To extend the system to chronic toxicity assessment, we examined the effects of the anti-hepatitis C virus (HCV) drug candidate BMS-986094, a guanosine nucleotide analogue, which was withdrawn from phase 2 clinical trials because of unexpected contractility toxicities. Additionally, we examined sofosbuvir, another nucleotide analogue inhibitor of HCV that has been approved as an anti-HCV drug. Motion imaging analysis revealed the difference in cardiotoxicity between the cardiotoxic BMS-986094 and the less toxic sofosbuvir in hiPSC-CMs, with a minimum of 4 days of treatment. In addition, we found that BMS-986094-induced contractility impairment was mediated by a decrease in calcium transient. These data suggest that chronic treatment improves the predictive power for the cardiotoxicity of anti-HCV drugs. Thus, hiPSC-CMs can be a useful tool to assess drug-induced chronic cardiotoxicity in non-clinical settings.
预测心血管系统的药物不良反应非常重要，因为它可能导致新药/候选药物的停药或已上市药物的撤市。虽然慢性评估心脏收缩力是安全药理学中的一个重要问题，但尚未完全开发出体外评估系统。我们之前开发了一种基于成像的收缩力测定系统，用于使用人诱导多能干细胞衍生的心肌细胞（hiPSC-CMs）检测急性心脏毒性。为了将该系统扩展到慢性毒性评估，我们研究了抗丙型肝炎病毒（HCV）候选药物 BMS-986094 的作用，这是一种鸟嘌呤核苷酸类似物，由于意外的收缩毒性而在 2 期临床试验中被撤回。此外，我们还研究了另一种 HCV 核苷酸类似物抑制剂索非布韦，它已被批准为抗 HCV 药物。运动成像分析显示，在 hiPSC-CMs 中，心脏毒性的 BMS-986094 和毒性较小的索非布韦之间存在差异，治疗时间至少为 4 天。此外，我们发现 BMS-986094 诱导的收缩力损伤是通过钙瞬变减少介导的。这些数据表明，慢性治疗提高了抗 HCV 药物心脏毒性的预测能力。因此，hiPSC-CMs 可以成为评估非临床环境中药物引起的慢性心脏毒性的有用工具。
