Pulmonary administration of remdesivir in the treatment of COVID-19
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Letter to Editor Pulmonary administration of remdesivir in the treatment of COVID-19 Henrik Berg Rasmussen,1,6 Peter Riis Hansen,2 Olivier Taboureau,3 Ragnar Thomsen,4 and Gesche Jürgens5
Received 19 July 2020; accepted 2 September 2020
We read, with great interest, the commentary “Remdesivir for Treatment of COVID-19: Combination of Pulmonary and IV Administration May Offer Additional Benefit” by Sun [1]. In this commentary, Sun [1] suggests that intravenous administration of remdesivir is unlikely to produce sufficiently high concentrations of its active antiviral agent, the nucleoside triphosphate (Nuc-TP), in human lungs to effectively eliminate SARS-CoV-2. This led Sun [1] to propose investigations into pulmonary delivery of remdesivir, modifications of its prodrug moiety, and use of nanoformulations of this agent to improve treatment of COVID-19 pneumonia. We consider that these issues are highly relevant but are uncertain about the conclusion that intravenous administration of remdesivir in the treatment of COVID-19 is unlikely to produce therapeutically effective concentrations of this prodrug and its active antiviral agent in human lungs. First, results from in vitro assays for assessment of the activity of antiviral agents vary substantially being highly dependent on viral quantification method, viral isolate, and cell type used for viral propagation [2, 3]. Sun [1] retrieved 50% and 90% maximal inhibitory concentrations (IC50 and IC90) of 0.77 and 1.76 μM, respectively, for the anti-SARS-CoV-2 activity of remdesivir in Vero E6 African green monkey kidney cells from a study by Wang et al. [4]. Assuming a 10-fold intracellular accumulation of Nuc-TP relative to extracellular remdesivir, these inhibitory values were used to derive the intracellular Nuc-TP IC50 and IC90 values of 7.7 and 17.6 μM, which were compared with an estimated intracellular Nuc-TP concentration in the range of 4 to 10 μM in human lungs [1]. However, other studies have reported IC50 and IC90 values for the anti-SARS-CoV-2 activity of remdesivir that differed from 1
Institute of Biological Psychiatry, Mental Health Centre Sct. Hans, Roskilde, Denmark. 2 Cardiology Department, Herlev and Gentofte Hospital, Hellerup, Denmark. 3 Université de Paris, INSERM U1133, CNRS UMR 8251, 75006, Paris, France. 4 Section of Forensic Chemistry, Department of Forensic Medicine, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark. 5 Clinical Pharmacology Unit, Roskilde Hospital, Roskilde, Denmark. 6 To whom correspondence should be addressed. (e–mail: [email protected])
those adopted by Sun. This includes the study by Pruijssers et al. [5] that reported IC50 values of 0.001 and 0.009 μM in primary human airway epithelial (HAE) cells in two independent experiments, whereas a higher IC50 value of 0.28 μM and an IC90 value of 2.48 μM were observed with Calu-3 2B4 respiratory epithelial cells. Pruijssers et al. [5] also found that remdesivir inhibited SARS-CoV2 with IC50 and IC90 values of 1.65 and 2.40 μM, respectively,
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