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.