Inhaled remdesivir reduces viral burden in a nonhuman primate model of SARS-CoV-2 infection

Autor: Meghan S. Vermillion, Eisuke Murakami, Bin Ma, Jared Pitts, Adrian Tomkinson, Davin Rautiola, Darius Babusis, Hammad Irshad, Dustin Seigel, Cynthia Kim, Xiaofeng Zhao, Congrong Niu, Jesse Yang, Andrew Gigliotti, Nani Kadrichu, John P. Bilello, Scott Ellis, Roy Bannister, Raju Subramanian, Bill Smith, Richard L. Mackman, William A. Lee, Philip J. Kuehl, Jim Hartke, Tomas Cihlar, Danielle P. Porter
Rok vydání: 2022
Předmět:
Zdroj: Science Translational Medicine. 14
ISSN: 1946-6242
1946-6234
DOI: 10.1126/scitranslmed.abl8282
Popis: Remdesivir (RDV) is a nucleotide analog prodrug with demonstrated clinical benefit in patients with coronavirus disease 2019 (COVID-19). In October 2020, the U.S. FDA approved intravenous RDV as the first treatment for hospitalized COVID-19 patients. Furthermore, RDV has been approved or authorized for emergency use in more than 50 countries. To make RDV more convenient for nonhospitalized patients earlier in disease, alternative routes of administration are being evaluated. Here, we investigated the pharmacokinetics and efficacy of RDV administered by head dome inhalation in African green monkeys (AGM). Relative to an intravenous administration of RDV at 10 mg/kg, an about 20-fold lower dose administered by inhalation produced comparable concentrations of the pharmacologically active triphosphate in lower respiratory tract tissues. Distribution of the active triphosphate into the upper respiratory tract was also observed after inhaled RDV exposure. Inhalation RDV dosing resulted in lower systemic exposures to RDV and its metabolites as compared with intravenous RDV dosing. An efficacy study with repeated dosing of inhaled RDV in an AGM model of SARS-CoV-2 infection demonstrated reductions in viral replication in bronchoalveolar lavage fluid and respiratory tract tissues compared with placebo. Efficacy was observed with inhaled RDV administered once daily at a pulmonary deposited dose of 0.35 mg/kg beginning about 8 hours after infection. Moreover, the efficacy of inhaled RDV was similar to that of intravenous RDV administered once at 10 mg/kg followed by 5 mg/kg daily in the same study. Together, these findings support further clinical development of inhalation RDV.
Databáze: OpenAIRE
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