Prolonged Exposure to Remdesivir Inhibits the Human Ether-a-go-go-related Gene Potassium Current

ABSTRACT

Introduction: Remdesivir is indicated for the treatment of COVID-19 in patients requiring hospitalization. However, cases of QTc interval prolongation and torsade de pointes (TdP) have been reported to the FDA Adverse Event Reporting System. Drug-induced QTc prolongation and TdP is the single most common cause of withdrawal, relabeling and use restriction of marketed drugs. Most drugs that prolong the QTc inhibit a potassium current (IKr), which is encoded by the human ether-a-go-go-related gene (hERG) and is crucial for ventricular repolarization and action potential duration. Research Question or Hypothesis: To assess the potential for remdesivir and its metabolite, GS441524, to inhibit hERG-related currents. Study Design: Cell-based hERG Assay Methods: Whole-cell, voltage-clamp experiments were performed in HEK-293 cells stably expressing hERG. Borosilicate glass electrodes (resistance 2-4 MW) filled with internal solution were used to record tail currents at depolarizing and repolarizing voltages tail current. To assess acute effects, drugs were added to the internal pipette solution, and for prolonged exposure;cells were incubated with remdesivir for 24 hours prior to recording. Results: Acute exposure to remdesivir and GS-441524 did not significantly inhibit peak activation or maximum tail current density. However, prolonged exposure to remdesivir 100 nM and 1 mM, but not 10 nM, inhibited peak activation currents by 32% (19±2 pA/pF, p = 0.03) and 36% (18±2 pA/pF, p = 0.02) respectively. Remdesivir 100 nM and 1 mM, also inhibited the maximum tail current density by 40% (18±2 pA/pF, p = 0.02) and 37% (19±2 pA/pF, p = 0.03), respectively. Conclusion: Prolonged exposure to physiological concentrations of remdesivir inhibits hERG-related currents. These results, coupled with clinical reports of QTc prolongation and TdP, highlight the need for a rigorous assessment of the effect of remdesivir on ventricular repolarization and risk of proarrhythmia.