目的:抗肿瘤药物引起的收缩功能障碍是抗癌治疗中断的主要原因。虽然靶向抗癌药物很少引起收缩功能障碍,它们与化学疗法的组合显着增加了发病率。人诱导的多能干细胞衍生的心肌细胞(hiPSC-CM)提供了一种有效的体外模型来评估心血管安全性。然而,基于hiPSC-CM定量预测射血分数的降低具有挑战性,因为缺乏机体对心肌细胞损伤的调节反应。
方法:这里,我们开发并验证了一个体外-体内翻译平台,以评估基于hiPSC-CM的抗肿瘤药物诱导的射血分数的降低。药物-心肌细胞相互作用,和系统反应。药物-心肌细胞相互作用被实现为基于机制的毒理学(TD)模型,然后将其整合到基于定量系统药理学-生理学的药代动力学(QSP-PBPK)模型中,以形成完整的翻译平台。通过比较多柔比星和曲妥珠单抗诱导的收缩功能障碍的模型预测和临床观察的发生率来验证该平台。
结果:共有33,418名虚拟患者纳入接受多柔比星和曲妥珠单抗单独或联合治疗。对于阿霉素,QSP-PBPK-TD模型成功捕获了收缩功能障碍发生率相对于累积剂量的总体趋势.对于曲妥珠单抗,单药治疗的预测发生率为0.31-2.7%,曲妥珠单抗-多柔比星序贯治疗的预测发生率为0.15-10%,涵盖临床报告中的观察结果(0.50-1.0%和1.5-8.3%,分别)。
结论:结论:体外-体内翻译平台能够预测收缩功能障碍的发生率,几乎仅仅依赖于hiPSC-CM,这可以促进优化抗肿瘤药物的治疗方案。
OBJECTIVE: Antineoplastic agent-induced systolic dysfunction is a major reason for interruption of anticancer treatment. Although targeted anticancer agents infrequently cause systolic dysfunction, their combinations with chemotherapies remarkably increase the incidence. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) provide a potent in vitro model to assess cardiovascular safety. However, quantitatively predicting the reduction of ejection fraction based on hiPSC-CMs is challenging due to the absence of the body\'s regulatory response to cardiomyocyte injury.
METHODS: Here, we developed and validated an in vitro-in vivo translational platform to assess the reduction of ejection fraction induced by antineoplastic drugs based on hiPSC-CMs. The translational platform integrates drug exposure, drug-cardiomyocyte interaction, and systemic response. The drug-cardiomyocyte interaction was implemented as a mechanism-based toxicodynamic (TD) model, which was then integrated into a quantitative system pharmacology-physiological-based pharmacokinetics (QSP-PBPK) model to form a complete translational platform. The platform was validated by comparing the model-predicted and clinically observed incidence of doxorubicin and trastuzumab-induced systolic dysfunction.
RESULTS: A total of 33,418 virtual patients were incorporated to receive doxorubicin and trastuzumab alone or in combination. For doxorubicin, the QSP-PBPK-TD model successfully captured the overall trend of systolic dysfunction incidences against the cumulative doses. For trastuzumab, the predicted incidence interval was 0.31-2.7% for single-agent treatment and 0.15-10% for trastuzumab-doxorubicin sequential treatment, covering the observations in clinical reports (0.50-1.0% and 1.5-8.3%, respectively).
CONCLUSIONS: In conclusion, the in vitro-in vivo translational platform is capable of predicting systolic dysfunction incidence almost merely depend on hiPSC-CMs, which could facilitate optimizing the treatment protocol of antineoplastic agents.