Remdesivir (RDV), a single diastereomeric monophosphoroamidate prodrug that inhibits viral RNA polymerases, has potent in vitro antiviral activity against SARS-CoV2. RDV received FDA’s emergency use authorization in United States and approval in Japan for treatment of severe COVID-19 patients. This report describes two phase 1 studies that evaluated the safety and pharmacokinetics (PK) of single escalating and multiple intravenous (IV) doses of RDV (solution or lyophilized formulation) in healthy subjects. Lyophilized formulation was evaluated for potential future use in clinical trials due to its storage stability in resource-limited settings. All adverse events were Grade 1 or 2 in severity. Overall, RDV exhibited a linear profile following single-dose IV administration over 2 hours of RDV solution formulation across the dose range of 3 to 225mg. Both lyophilized and solution formulations provided comparable PK parameters. High intracellular concentrations of the active triphosphate (approximately 220 to 370- fold higher than the in vitro EC50 against SARS-CoV-2 clinical isolate) were achieved following infusion of 75 mg or 150 mg lyophilized formulation over 30 minutes or 2 hours. Following multiple-doses of RDV 150mg once daily for 7 or 14 days, RDV exhibited a PK profile similar to single-dose administration. Metabolite GS-441524 accumulated approximately 1.9-fold after daily dosing. Overall, RDV exhibited favorable safety and PK profiles that supported once-daily dosing.Reference:
Humeniuk, R., Mathias, A., Cao, H., Osinusi, A., Shen, G., Chng, E., Ling, J., Vu, A. and German, P. (2020) Safety, Tolerability, and Pharmacokinetics of Remdesivir, an Antiviral for Treatment of COVID-19, in Healthy Subjects. Clinical and Translational Science. 26th June. https://doi.org/10.1111/cts.12840 (epub ahead of print).