Investigational Treatments for COVID‐19 may Increase Ventricular Arrhythmia Risk Through Drug Interactions

Figure 1. Concentration‐dependent effects of coronavirus disease 2019 (COVID‐19) drugs on ventricular action potentials. (a) Heatmap illustrating the extent to which azithromycin (AZ), chloroquine (CQ), ritonavir (RT), and lopinavir (LP) inhibit 7 important cardiac ionic currents, as previously measured by Crumb et al. 16 These authors reported effective free therapeutic plasma concentration (EFTPC) of each drug, in addition to half maximal inhibitory concentration (IC50) values that indicated how much each drug influenced 7 cardiac ionic currents (see Methods for abbreviations). Block of currents by particular drugs at 10*EFTPC was calculated based on drug concentration and IC50 values using a simple pore block model. (b) Simulations with the baseline myocyte model demonstrating how each drug, at 10*EFTPC, is predicted to influence ventricular action potentials (APs). (c) Concentration‐response curves illustrating how the 4 drugs influence AP duration (APD), the duration between the action potential upstroke (maximal rate of change of voltage) and 90% repolarization. Drug concentrations tested ranged from 0.3 times to 10 times EFTPC, with logarithmically spaced increments. (d) Predicted…

Figure 2. Simulated population pharmacokinetics of coronavirus disease 2019 (COVID‐19) drugs. (a) Simulations show that plasma concentrations of lopinavir (LP) are greater with co‐administration of ritonavir (RT) than when the former drug is given alone. (b) Predicted free plasma concentrations of LP under standard dosing regimen with RT. (c) Predicted free plasma concentrations of RT under standard dosing regimen with LP. (d) Predicted free plasma concentrations of chloroquine under standard dosing regimen. (e) Predicted free plasma concentrations of azithromycin under standard dosing regimen. In b–e, the thick line indicates the median individual within a virtual population of 1,000 (gray shaded area), the red dashed line indicates mean peak concentration of the 5% of the patients with highest drug concentrations, and additional dashed lines indicate IC50 values for cardiac ion channel inhibition.

Figure 3. Sex differences and cardiac disease influence cardiac effects of coronavirus disease 2019 (COVID‐19) drugs. (a) With the baseline model defined as the healthy male myocyte, bars illustrate alterations to model parameters that were implemented to simulate myocytes from healthy female, diseased male, and diseased female hearts. Y‐axis represents natural logarithm of the fold change in each parameter such that increases are positive and decreases are negative (i.e., an increase in a parameter by a factor of e (2.718) would be represented as + 1). (b) Effects of clinical concentrations of lopinavir plus ritonavir in the four groups where black dashed lines are action potentials (Aps) with no drug, and solid colored lines show effects of drugs. (c) Effects of clinical concentrations of chloroquine plus azithromycin in the four groups. In both cases, simulated action potential prolongation was greatest in the baseline female heart failure (HF) myocyte.

Figure 4. Virtual population simulations and arrhythmia susceptibility in female heart failure group. (a) Virtual population simulations of the four groups, as indicated. Each panel shows 20 action potentials (APs) from the population of 1,000. (b) Distributions of drug‐induced action potential prolongation (ΔAPD) by different drug combinations, in the four populations, as indicated. With chloroquine + azithromycin treatment, arrhythmic dynamics were observed in 1 cell (healthy male), 16 cells (HF male), 19 cells (healthy female), and 85 cells (HF female) from each 1,000 cell population. (c) Parameter sensitivity values obtained from logistic regression analysis of the HF female population. Parameters are rank ordered from greatest to least effect on arrhythmic dynamics, and are color‐coded based on whether an increase in a parameter will increase or decrease the arrhythmia probability. (d) Simulation results comparing two cells from the HF female population to indicate the importance of Na+‐Ca2+ exchange (NCX) in determining arrhythmia susceptibility. Results show action potentials before (dashed black line) and after (colored lines) application of chloroquine + azithromycin. The two…