Thorough QT/QTc Clinical Study to Evaluate the Effect of Remdesivir on Cardiac Repolarization in Healthy Participants.

摘要

QT interval prolongation associated with drug administration is an important consideration in drug development. Patients with COVID-19 are at increased risk for cardiac complications, and QT interval prolongation correlates with higher mortality. This Phase 1 study evaluated the safety, tolerability, pharmacokinetics, and potential effects on QT interval corrected for heart rate (QTc) of a single supratherapeutic intravenous dose of remdesivir (600 mg; 3 times the loading dose [200 mg] of the approved regimen) in healthy participants, as well as the safety of its solubilizing excipient sulfobutylether-β-cyclodextrin. The study included 2 cohorts: a dose-selection cohort (sentinel cohort), followed by a partially blinded, randomized, placebo- and positive-controlled, 3-period, 6-treatment sequence, single-dose crossover cohort (TQT cohort). The clinical endpoints were adverse events (AEs), laboratory abnormalities, plasma pharmacokinetic parameters of remdesivir and its metabolites, ΔΔQTcF (baseline-adjusted, placebo-corrected QT interval corrected for heart rate using the Fridericia formula) at each postdose time point, and the relationship between ΔΔQTcF and plasma concentrations of remdesivir by concentration-QT analysis. Sixty participants completed the study. Plasma pharmacokinetics of remdesivir and its metabolites showed no significant differences between cohorts. Sulfobutylether-β-cyclodextrin was cleared within 24 h, with no pharmacokinetic non-linearities observed. The study found no clinically relevant QTc prolongation from remdesivir at a supratherapeutic dose (ΔΔQTcF < 10 ms). Most AEs were Grade 1 or 2 in severity. No serious AEs or deaths were reported. These findings suggest that a single 600-mg intravenous dose of remdesivir is generally safe and well tolerated and does not lead to QTc prolongation of safety concern.