Applying the CiPA approach to evaluate cardiac proarrhythmia risk of some antimalarials used off‐label in the first wave of COVID‐19

Abstract

We applied a set of in silico and in vitro assays, compliant with the CiPA (Comprehensive In Vitro Proarrhythmia Assay) paradigm, to assess the risk of chloroquine or hydroxychloroquine‐mediated QT prolongation and Torsades de Pointes (TdP), alone and combined with erythromycin and azithromycin, drugs repurposed during the first wave of COVID‐19. Each drug or drug combination was tested in patch clamp assays on 7 cardiac ion channels, in in silico models of human ventricular electrophysiology (Virtual Assay ® ) using control (healthy) or high‐risk cell populations, and in human induced pluripotent stem cell (hiPSC)‐derived cardiomyocytes. In each assay, concentration‐response curves encompassing and exceeding therapeutic free plasma levels were generated. Both chloroquine and hydroxychloroquine showed blocking activity against some potassium, sodium and calcium currents. Chloroquine and hydroxychloroquine inhibited I Kr (IC 50 : 1µM and 3‐7µM, respectively) and I K1 currents (IC 50 : 5 and 44µM, respectively). When combining hydroxychloroquine with azithromycin, no synergistic effects were observed. The two macrolides had no or very weak effects on the ion currents (IC 50 >300‐1000µM). Using Virtual Assay ® , both antimalarials affected several TdP indicators, chloroquine being more potent than hydroxychloroquine. Effects were more pronounced in the high‐risk cell population. In hiPSC‐derived cardiomyocytes, all drugs showed early‐after‐depolarizations, except azithromycin. Combining chloroquine or hydroxychloroquine with a macrolide did not aggravate their effects. In conclusion, our integrated nonclinical CiPA dataset confirmed that, at therapeutic plasma concentrations relevant for malaria or off‐label use in COVID‐19, chloroquine and hydroxychloroquine use is associated with a proarrhythmia risk, which is higher in populations carrying predisposing factors but not worsened with macrolide combination.

HPC framework for in-silico trials on 3D virtual human cardiac population to assess drug-induced arrhythmic risk

“…At a peak plasma concentration after the administration of 800 mg of HCQ, the risk for arrhythmic events was calculated as 43.7%. The virtual clinical trial was able to confirm that the use of HCQ was associated with a proarrhythmic risk, but it did not worsen when it was used in combination with AZM as has been observed clinically and experimentally [10,31,32]. It is important to stress that the concentrations tested within these virtual healthy patients were peak plasma concentrations, therefore representing their effects at a discrete high plasma concentrations, or "worst case" scenarios.…”

“…A variety of computational methods have been an important component for the study and assessment of drug-induced arrhythmias [8,9,10,11]. The work by Yang et al [8] has employed computational methods from the atomistic level to the tissue level.…”

“…The work by Bottino et al [9] and Beattie et al [11], include computational simulations up to the the tissue level. The work by Delaunois et al [10] include both experimental assays and 0-D electrophysiology simulations to assess proarrhythmic risk. Other works also include full heart simulations for pro-arrhythmia assessment [21] of a single subject.…”

Quantifying arrhythmic long QT effects of hydroxychloroquine and azithromycin with whole-heart optical mapping and simulations

“…The magnitudes of reduction in ionic currents in our simulations are well within the experimentally observed values in HCQ- and AZM-treated hearts and the theoretical values calculated using the Hill’s equation from the in vitro measurements of half-maximal inhibitory concentrations of HCQ and AZM when applied to different ionic channels. 28 …”

Use of hiPSC-derived cardiomyocytes to rule out proarrhythmic effects of drugs: the case of hydroxychloroquine in COVID-19

“…Platforms to guide clinical decision making and orient research efforts are required, particularly in critical situations when there is a compelling need for repurposed compounds or when therapies are being recommended for home use. In 6 recent years, the use of hiPSC-CMs for safety pharmacology has progressively gained momentum and multiple validation strategies have been attempted to generate experimental models with enhanced predictive potential, and recently the CiPA approach or similar strategies have been used to evaluate the proarrhythmic risk of HCQ on hiPSC-CMs from commercial hiPSC lines or healthy individuals (Delaunois et al, 2021). Platforms based on hiPSCs can offer rapid and relevant readouts for safety pharmacology (Sala et al, 2017a) but the possibility of incorporating patient-specific drug responses in addition to those from healthy individuals can increase the predictive capacity of these platforms in conditions where prompt actions are required.…”