Safety, Tolerability, and Pharmacokinetics of Remdesivir, An Antiviral for Treatment of COVID‐19, in Healthy Subjects

Abstract

Remdesivir (RDV), a single diastereomeric monophosphoramidate prodrug that inhibits viral RNA polymerases, has potent in vitro antiviral activity against severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2). RDV received the US Food and Drug Administration (FDA)’s emergency use authorization in the United States and approval in Japan for treatment of patients with severe coronavirus disease 2019 (COVID‐19). This report describes two phase I studies that evaluated the safety and pharmacokinetics (PKs) of single escalating and multiple i.v. 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 i.v. administration over 2 hours of RDV solution formulation across the dose range of 3–225 mg. Both lyophilized and solution formulations provided comparable PK parameters. High intracellular concentrations of the active triphosphate (~ 220‐fold to 370‐fold higher than the in vitro half‐maximal effective concentration 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 150 mg once daily for 7 or 14 days, RDV exhibited a PK profile similar to single‐dose administration. Metabolite GS‐441524 accumulated ~ 1.9‐fold after daily dosing. Overall, RDV exhibited favorable safety and PK profiles that supported once‐daily dosing.

Cardiac Adverse Events With Remdesivir in COVID-19 Infection

“…Many pitfalls still exist with understanding COVID-19 and the use of remdesivir. Optimum time of administration in relation of the benefit of remdesivir for COVID-19 has yet to be clear, although initiation is generally considered once oxygen saturations drop below 94% [1,2,8,14]. Both of our patients developed sinus bradycardia within 20-40 minutes of infusion time (at drug peaks), and typically doses are infused over a full hour to completion [8].…”

“…It is possible that it contributed to the prolongation of the QT interval in this patient despite having been discontinued shortly before remdesivir initiation. Remdesivir itself has been mentioned in its own right to have an effect on the QT interval, but more studies are needed to support a causality [8,10,12]. Cardiac disturbances in COVID-19 patients receiving remdesivir seem to be primarily due to bradycardia or hypotension in the studies found and less commonly being due to QT prolongation [4,5,10,14,15].…”

“…Optimum time of administration in relation of the benefit of remdesivir for COVID-19 has yet to be clear, although initiation is generally considered once oxygen saturations drop below 94% [1,2,8,14]. Both of our patients developed sinus bradycardia within 20-40 minutes of infusion time (at drug peaks), and typically doses are infused over a full hour to completion [8]. The coronavirus' also have a favorable profile toward the development of remdesivir resistance, which may explain why 5 days of therapy is commonly utilized over 10 days [7].…”

Toward Consensus on Correct Interpretation of Protein Binding in Plasma and Other Biological Matrices for COVID‐19 Therapeutic Development

“…Thus, a consideration of free drug concentrations in other relevant matrices is likely to be needed to underpin successful therapeutic development, but a lack of standardised methodology complicated robust investigation. Figure 1B shows the mean plasma concentration time profile for remdesivir following multiple dose administration of 150mg to healthy volunteers (30). The free drug fraction of remdesivir in human plasma has been reported as 0.121 (12.1%) (31) and this value has been used to derive the unbound plasma profile, which is also shown in Figure 1B.…”

Aptamer BC 007 - Efficient binder of spreading-crucial SARS-CoV-2 proteins

“…With respect to drug development, it is anti-viral drugs, especially those which are known from former endeavours to fight against human immunodeficiency virus or other viral infections, targeting replication-crucial proteins to interfere with viral replication such as protease inhibitors, reverse transcriptase or endonuclease inhibitors [ 1 , 2 ]. An inhibitor of the RNA dependent RNA polymerase, Remdesivir [ 3 ], which was originally under development for the combat of Ebola has already been approved for its use in COVID-19.…”