Many drugs that have been proposed for treatment of COVID-19 are reported to cause cardiac adverse events, including ventricular arrhythmias. In order to properly weigh risks against potential benefits, particularly when decisions must be made quickly, mathematical modeling of both drug disposition and drug action can be useful for predicting patient response and making informed decisions. Here we explored the potential effects on cardiac electrophysiology of 4 drugs proposed to treat COVID-19: lopinavir, ritonavir, chloroquine, and azithromycin, as well as combination therapy involving these drugs. Our study combined simulations of pharmacokinetics (PK) with quantitative systems pharmacology (QSP) modeling of ventricular myocytes to predict potential cardiac adverse events caused by these treatments. Simulation results predicted that drug combinations can lead to greater cellular action potential prolongation, analogous to QT prolongation, compared with drugs given in isolation. The combination effect can result from both pharmacokinetic and pharmacodynamic drug interactions. Importantly, simulations of different patient groups predicted that females with pre-existing heart disease are especially susceptible to drug-induced arrhythmias, compared males with disease or healthy individuals of either sex. Overall, the results illustrate how PK and QSP modeling may be combined to more precisely predict cardiac risks of COVID-19 therapies.

中文翻译：

---

对COVID-19的研究性治疗可能会通过药物相互作用增加室性心律失常的风险。

据报道，许多已提议用于治疗COVID-19的药物会引起心脏不良事件，包括室性心律失常。为了恰当地权衡风险与潜在收益之间的关系，尤其是在必须快速做出决策时，药物处置和药物作用的数学模型对于预测患者的反应和做出明智的决策非常有用。在这里，我们探讨了建议用于治疗COVID-19的4种药物对心脏电生理的潜在影响：洛匹那韦，利托那韦，氯喹和阿奇霉素，以及涉及这些药物的联合治疗。我们的研究将心室肌细胞的药代动力学（PK）模拟与定量系统药理学（QSP）模型相结合，以预测由这些治疗引起的潜在心脏不良事件。模拟结果预测，与单独给予药物相比，药物组合可导致更大的细胞动作电位延长，类似于QT延长。组合作用可以由药代动力学和药效学药物相互作用产生。重要的是，对不同患者群体的模拟预测，与患有疾病的男性或任何性别的健康人相比，患有心脏病的女性特别容易患上药物性心律失常。总的来说，这些结果说明了如何将PK和QSP建模相结合以更精确地预测COVID-19治疗的心脏风险。组合作用可以由药代动力学和药效学药物相互作用产生。重要的是，对不同患者群体的模拟预测，与患有疾病的男性或任何性别的健康人相比，患有心脏病的女性特别容易患上药物性心律失常。总的来说，这些结果说明了如何将PK和QSP建模相结合以更精确地预测COVID-19治疗的心脏风险。组合作用可以由药代动力学和药效学药物相互作用产生。重要的是，对不同患者群体的模拟预测，与患有疾病的男性或任何性别的健康人相比，患有心脏病的女性特别容易患上药物性心律失常。总的来说，这些结果说明了如何将PK和QSP建模相结合以更精确地预测COVID-19治疗的心脏风险。