Key result
COVID-19 drug combinations exacerbate simulated repolarization prolongation, with females with heart failure at highest risk.
Why the study?
Many drugs proposed for COVID-19 treatment are reported to cause cardiac adverse events including ventricular arrhythmias, necessitating prediction of patient response to weigh risks and benefits.
May increase arrhythmia risk with COVID-19 drug combinations in females with heart failure; leaves open need for clinical validation.
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.
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Varshneya et al. (2020) studied COVID-19 (Cardiac safety of treatments) (n=4,000). COVID-19 investigational treatments (lopinavir, ritonavir, chloroquine, azithromycin) vs. Individual drugs vs combinations was evaluated on Action potential duration at 90% repolarization (ΔAPD90). Simulations predicted that combinations of COVID-19 drugs (lopinavir+ritonavir or chloroquine+azithromycin) cause greater action potential prolongation than individual drugs, with females with heart failure at highest risk for arrhythmias.
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