REMDESIVIR (VEKLURY) FOR TREATING COVID-19 PATIENTS: WHAT TO EXPECT FROM A CARDIAC ELECTROPHYSIOLOGICAL PERSPECTIVE

Abstract

BACKGROUNDRemdesivir was authorized with conditions in Canada on July 27, 2020 for the treatment of severe COVID-19 in adults and youth (aged ≥ 12 years) with pneumonia requiring supplemental oxygen. In the Canadian Veklury® monograph, it is mentioned that current non-clinical and clinical data do not suggest a risk of QT prolongation, but QT prolongation has not been fully evaluated in humans. Interestingly, in a recent small series of 67 patients treated with remdesivir alone daily (200 mg Day 1, 100 mg Days 2-7); although no instance of torsades de pointes was reported, there was a mean 24.4-ms increase in the QTc, with 9% of all QTc ≥ 500 ms and 9% of all DQTc ≥ 60 ms. Our aim was therefore to further evaluate the effects of remdesivir on cardiac electrophysiology.METHODS AND RESULTS1) Ex vivo Langendorff retroperfusion experiments: Isolated hearts from male Hartley guinea pigs were either let at their natural sinus rhythm (SR) or paced at basic cycle lengths (BCL) of 250 or 200 ms. They were allowed to stabilize and were then exposed for 15 minutes to either remdesivir 3 (n=7), 10 (n=7) or 30 (n=5) µmol/L to assess drug-induced effect on monophasic action potential duration measured at 90% repolarization (MAPD90). 2) In vivo wireless cardiac telemetry experiments: Guinea pigs (n=3) implanted with radio transmitters were administered i.p. daily doses of remdesivir (5 mg/kg on Day 1 and 2.5 mg/kg on Days 2-10) and continuous ECG recordings were made. Results: See Tables.CONCLUSIONPrevious clinical studies have shown peak plasma concentrations of remdesivir in the 5-10 µmol/L range after the 200 mg Day 1 dose. In the present study, remdesivir had hardly any significant ex vivo effect on MAPD90 at clinically relevant concentrations (3-30 µmol/L). However, in vivo, the drug caused significant prolongation of the QT at Day 1 and Day 10 and of QTcF at Day 10. Interestingly, a trend toward bradycardia was observed in vivo after each administration of remdesivir. More in vivo experiments are therefore required to rule out any QTc-prolonging effects of remdesivir at clinically recommended dosage.