Remdesivir for Treatment of COVID-19: Combination of Pulmonary and IV Administration May Offer Aditional Benefit
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Commentary Remdesivir for Treatment of COVID-19: Combination of Pulmonary and IV Administration May Offer Aditional Benefit Duxin Sun1,2
Received 7 April 2020; accepted 13 April 2020 Abstract. Remdesivir is one of the most promising drugs to treat COVID-19 based on the following facts: remdesivir has a broad-spectrum antiviral mechanism of action; it demonstrated in vitro activity against SARS-CoV-2 and in vivo efficacy in animal models against the similar coronavirus MERS-CoV; its safety profile has been tested in Ebola patients and in compassionate use in COVID-19 patients. Currently, remdesivir is being investigated in ten randomized controlled trials against COVID-19. The dose regimen of remdesivir is an IV loading dose of 200 mg on day 1 followed by daily IV maintenance doses of 100 mg for 5–9 days. Based on our data analysis, however, remdesivir with IV administration alone is unlikely to achieve excellent clinical efficacy. This analysis is based on the following observations: plasma exposures of remdesivir and its active metabolite are unlikely to be correlated with its clinical efficacy; remdesivir and its active metabolites are unlikely to be adequate in the lung to kill the SARS-CoV-2 virus. Even if remdesivir demonstrates benefits in the current randomized controlled trials, its efficacy may be limited. We suggest that a combination of an IV and pulmonary delivery dose regimen should be studied immediately to realize a potentially more effective antiviral therapy against COVID-19. KEY WORDS: clinical trials; COVID-19; drug metabolism; pharmacokinetics; pneumonia; pulmonary delivery; remdesivir; SARS-CoV-2.
The pandemic of coronavirus disease 2019 (COVID-19) is not showing any signs of slowing down, and it may become a seasonal disease. Therefore, it is critical to develop therapies for COVID-19. Currently, remdesivir is being investigated against COVID-19 in ten randomized controlled trials. The dose regimen of remdesivir is an IV loading dose of 200 mg on day 1 followed by daily IV maintenance doses of 100 mg for 5–9 days (https://clinicaltrials.gov/ ). Several reports strongly suggest remdesivir would be efficacious against COVID-19. (a) Remdesivir has broad-spectrum of antiviral activity by inhibiting viral RNA synthesis [1]. (b) Remdesivir has demonstrated in vitro antiviral activity (IC50 0.77 μM) against SARS-CoV-2 [2]. (c) Studies of remdesivir have shown efficacy against other coronaviruses such as Middle East Respiratory Syndrome (MERS) virus MERS-CoV in vitro and in mice and monkeys [3–5]. (d) The current IV dose regimen of remdesivir was evaluated in a randomized controlled trial in human Ebola patients with some limited efficacy [6] and in a compassionate use in one COVID-19 patient [7]. During the time when this commentary was reviewed, an observational study of the compassionate use of remdesivir in
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Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, USA. 2 To whom correspondence should be addressed. (e–mail: [email protected])
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