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

Rita Humeniuk, Anita Mathias, Huyen Cao, Anu Osinusi, Gong Shen, Estelle Chng, John Ling, Amanda Vu, Polina German, Rita Humeniuk, Anita Mathias, Huyen Cao, Anu Osinusi, Gong Shen, Estelle Chng, John Ling, Amanda Vu, Polina German

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.

Conflict of interest statement

The authors are employees of Gilead Sciences.

© 2020 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf the of American Society for Clinical Pharmacology and Therapeutics.

Figures

Figure 1
Figure 1
Plasma concentration‐vs‐time profiles following RDV single‐dose administration; mean (±SD) values are plotted. LLOQ, lower limit of quantification; RDV, remdesivir.
Figure 2
Figure 2
Plasma concentration‐vs‐time profiles following RDV multiple‐dose administration; mean (±SD) values are plotted. LLOQ, lower limit of quantification; RDV, remdesivir.

References

    1. Woo, P.C. , Lau, S.K. , Huang, Y. & Yuen, K.Y. Coronavirus diversity, phylogeny and interspecies jumping. Exp. Biol. Med. (Maywood). 234, 1117–1127 (2009).
    1. Denison, M.R. , Graham, R.L. , Donaldson, E.F. , Eckerle, L.D. & Baric, R.S. Coronaviruses: an RNA proofreading machine regulates replication fidelity and diversity. RNA Biol. 8, 270–279 (2011).
    1. Fehr, A.R. & Perlman, S. Coronaviruses: an overview of their replication and pathogenesis. Methods Mol. Biol. 1282, 1–23 (2015).
    1. Sheahan, T.P. et al Broad‐spectrum antiviral GS‐5734 inhibits both epidemic and zoonotic coronaviruses. Sci. Transl. Med. 9, 396 (2017).
    1. Tang, Q. , Song, Y. , Shi, M. , Cheng, Y. , Zhang, W. & Xia, X.Q. Inferring the hosts of coronavirus using dual statistical models based on nucleotide composition. Sci. Rep. 5, 17155 (2015).
    1. Lu, R. et al Genomic characterization and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet 395, 565–574 (2020).
    1. Contini, C. et al The novel zoonotic COVID‐19 pandemic: an expected global health concern. J. Infect. Dev. Ctries. 14, 254–264 (2020).
    1. Lake, M.A. What we know so far: COVID‐19 current clinical knowledge and research. Clin. Med. (Lond). 20, 124–127 (2020).
    1. Zhou, P. et al A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 579, 270–273 (2020).
    1. World Health Organization, Rolling updates on coronavirus disease (COVID‐19) (2020). <>. Accessed June 15, 2020.
    1. Rothan, H.A. & Byrareddy, S.N. The epidemiology and pathogenesis of coronavirus disease (COVID‐19) outbreak. J. Autoimmun. 109, 102433 (2020).
    1. Zhou, M. , Zhang, X. & Qu, J. Coronavirus disease 2019 (COVID‐19): a clinical update. Front. Med. 14, 126–135 (2020).
    1. Verity, R. et al Estimates of the severity of coronavirus disease 2019: a model‐based analysis. Lancet Infect. Dis. 20, 669–677 (2020).
    1. Johns Hopkins University and Medicine Coronavirus Resource Center (2020). <>. Accessed June 15, 2020.
    1. Cho, A. et al Synthesis and antiviral activity of a series of 1'‐substituted 4‐aza‐7,9‐dideazaadenosine C‐nucleosides. Bioorg. Med. Chem. Lett. 22, 2705–2707 (2012).
    1. Gordon, C.J. , Tchesnokov, E.P. , Feng, J.Y. , Porter, D.P. & Gotte, M. The antiviral compound remdesivir potently inhibits RNA‐dependent RNA polymerase from Middle East respiratory syndrome coronavirus. J. Biol. Chem. 295, 4773–4779 (2020).
    1. Gordon, C.J. et al Remdesivir is a direct‐acting antiviral that inhibits RNA‐dependent RNA polymerase from severe acute respiratory syndrome coronavirus 2 with high potency. J. Biol. Chem. 295, 6785–6797 (2020).
    1. Pruijssers, A. et alRemdesivir potently inhibits SARS‐CoV‐2 in human lung cells and chimeric SARS‐CoV expressing the SARS‐CoV‐2 RNA polymerase in mice. <>.
    1. US Food and Drug Administration, Emergency Use Authorization (2020). <>. Accessed June 15, 2020.
    1. Warren, T.K. et al Therapeutic efficacy of the small molecule GS‐5734 against Ebola virus in rhesus monkeys. Nature 531, 381–385 (2016).
    1. de Wit, E. et al Prophylactic and therapeutic remdesivir (GS‐5734) treatment in the rhesus macaque model of MERS‐CoV infection. Proc. Natl. Acad. Sci. USA 117, 6771–6776 (2020).
    1. Goldman, J.D. et al Remdesivir for 5 or 10 days in patients with severe COVID‐19. N. Engl. J. Med.. 10.1056/NEJMoa2015301. [epub ahead of print].
    1. Beigel, J.H. et al Remdesivir for the treatment of covid‐19 — preliminary report. N. Engl. J. Med. .
    1. Gilead Press Release (2020). <>. Accessed June 15, 2020.
    1. US Food and Drug Administration, Estimating the maximum safe starting dose in initial clinical trials for therapeutics in adult healthy volunteers (2005). <>. Accessed June 15, 2020.
    1. Maganti, L. , Panebianco, D.L. & Maes, A.L. Evaluation of methods for estimating time to steady state with examples from phase 1 studies. AAPS J. 10, 141–147 (2008).
    1. Dhama, K. et al COVID‐19, an emerging coronavirus infection: advances and prospects in designing and developing vaccines, immunotherapeutics, and therapeutics. Hum. Vaccin. Immunother. 16, 1232–1238 (2020). 10.1080/21645515.2020.1735227.
    1. AminJafari, A. & Ghasemi, S. The possible of immunotherapy for COVID‐19: a systematic review. Int. Immunopharmacol. 83, 106455 (2020).
    1. Lodise, T.P. & Rybak, M.J. COVID‐19: important therapy considerations and approaches in this hour of need. Pharmacotherapy 40, 379–381 (2020).
    1. Wang, M. et al Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019‐nCoV) in vitro. Cell Res. 30, 269–271 (2020).

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