Human bronchopulmonary disposition and plasma pharmacokinetics of oral bemnifosbuvir (AT-527), an experimental guanosine nucleotide prodrug for COVID-19

Abstract

ABSTRACTBemnifosbuvir (BEM, AT-527) is a novel oral guanosine nucleotide antiviral drug for the treatment of patients with COVID-19. Direct assessment of drug disposition in the lungs, via bronchoalveolar lavage, is necessary to ensure antiviral drug levels at the primary site of SARS-CoV-2 infection are achieved. We conducted a Phase 1 study in healthy subjects to assess the bronchopulmonary pharmacokinetics, safety, and tolerability of repeated doses of BEM. A total of 24 subjects were assigned to receive twice-daily (BID) BEM at doses of 275, 550, or 825 mg for up to 3.5 days. AT-511, the free base of BEM, was largely eliminated from the plasma within 6 h post dose in all dosing groups. Antiviral drug levels of BEM were consistently achieved in the lungs with BEM 550 mg BID. The mean level of the guanosine nucleoside metabolite AT-273, the surrogate of the active triphosphate metabolite of the drug, measured in the epithelial lining fluid of the lungs was 0.62 µM at 4–5 h post dose. This exceeded the targetin vitro90% effective concentration (EC90) of 0.5 µM for antiviral drug exposure against SARS-CoV-2 replication in human airway epithelial cells. BEM was well tolerated across all doses tested, and most treatment-emergent adverse events reported were mild in severity and resolved. The favorable pharmacokinetics and safety profile of BEM demonstrates its potential as an oral antiviral treatment for COVID-19, with 550 mg BEM BID currently under further clinical evaluation in patients with COVID-19.