Comprehensive preclinical evaluation of how cardiac safety profiles of potential COVID-19 drugs are modified by disease associated factors

TeBay C, McArthur J, Mangala M, Kerr N, Heitmann S, Matthew Perry M, Windley M, VaAndenberg J, Hill A.

Preprint, 2021

Summary:

The potential proarrhythmic potential effects of hydroxychloroquine and chloroquine as a proposed treatment for COVID-19 is unknown.  Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) derived were used to evaluate the effects of cardiac repolarization.  High-throughput electrophysiology recorded with Axion's MEA platform was used to determine the potency of hERG block in the presence of variable environmental factors.  Chloroquine and hydroxychloroquine indicated proarrhythmic risk at concentrations effective against SARS-CoV-2 in vitro.  The risk was further increased with hypokalaemia and hypermagnesemia while acidosis reduced the potency of the drugs.  In silico simulations exhibited action potential durations increase that equated to significant QT prolongation.  The authors concluded that there is a significant proarrhythmic risk for hydroxychloroquine and chloroquine at doses suggested to treat COVID-19, especially for patients with electrolyte imbalances.