Comprehensive preclinical evaluation of how cardiac safety profiles of
potential COVID-19 drugs are modified by disease associated factors.
Background and Purpose: Hydroxychloroquine and chloroquine, alone or in
combination with azithromycin, have been proposed as therapies for
COVID-19. However, there is currently scant and inconsistent data
regarding their proarrhythmic potential in these patients. Moreover,
their risk profile in the setting of altered physiological states
encountered in patients with COVID-19 (i.e. febrile state, electrolyte
imbalances, and/or acidosis) is unknown. Experimental approach: Potency
of hERG block was measured using high-throughput electrophysiology in
the presence of variable environmental factors. These potencies informed
simulations to predict population risk profiles. Effects on cardiac
repolarisation were verified in human induced pluripotent stem
cell-derived cardiomyocytes (hiPSC-CM) from three separate individuals.
Key Results: Chloroquine and hydroxychloroquine blocked hERG with IC50
of 1.47±0.07 µM and 3.78±0.17 µM respectively, indicating proarrhythmic
risk at concentrations effective against SARS-CoV-2 in vitro and
proposed in COVID-19 clinical trials. Hypokalaemia and hypermagnesemia
increased potency of chloroquine and hydroxychloroquine, indicating
increased proarrhythmic risk. Acidosis significantly reduced potency of
all drugs (i.e. reduced proarrhythmic risk), whereas increased
temperature decreased potency of chloroquine and hydroxychloroquine but
increased potency for azithromycin. In silico simulations across
genetically diverse populations predicted that 17% of individuals
exhibit action potential durations >500 ms at the highest
proposed therapeutic levels, equating to significant QT prolongation.
Conclusion and Implications: Significant proarrhythmic risk is predicted
for hydroxychloroquine and chloroquine at doses proposed to treat
COVID-19. Clinicians should carefully consider the risk of such
treatments, and implement long term QT interval monitoring in trials,
particularly in patients with electrolyte imbalances.