Figure 1:

(A) Heatmap illustrating the extent to which azithromycin (AZ), chloroquine (CQ), ritonavir (RT), and lopinavir (LP) inhibit 6 important cardiac ionic currents, as previously measured.¹² Reference 11 reported effective free therapeutic plasma concentration (EFTPC) of each drug, in addition to IC₅₀ values that indicated how much each drug influenced 6 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 simulated at 10*EFTPC are predicted to influence ventricular action potentials (APs). (C) Concentration-response curves illustrating how the 4 drugs influence APD₉₀, 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 AP prolongation (ΔAPD₉₀) for chloroquine + azithromycin. (E) Predicted ΔAPD₉₀ for lopinavir + ritonavir. Combination therapy causes greater AP prolongation than drugs applied individually, as shown in both heatmaps illustrating ΔAPD₉₀ over a range of drug concentrations, and in example AP traces showing effects at 3*EFTPC.