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All Studies   Meta Analysis    Recent:   

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

Jan 2024  
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Phase 1 study showing effective lung delivery and safety of the oral COVID-19 antiviral candidate bemnifosbuvir (AT-527) at 550mg twice daily. Authors found AT-527 550mg BID achieved sustained antiviral drug levels in lung fluids that exceeded the EC90 target concentration of 0.5μM required to inhibit SARS-CoV-2 replication in human airway cells. AT-527 underwent rapid systemic clearance but good lung distribution, with the active metabolite detected in alveolar macrophages. The 550mg BID regimen was well tolerated over 3.5 days with mostly mild adverse effects.
Zhou et al., 8 Jan 2024, preprint, 9 authors, trial NCT04877769 (history). Contact: zhou.xj@ateapharma.com.
This PaperBemnifosbuvirAll
Human bronchopulmonary disposition and plasma pharmacokinetics of oral bemnifosbuvir (AT-527), an experimental guanosine nucleotide prodrug for COVID-19
Xiao-Jian Zhou, Arantxa Horga, Adeep Puri, Lee Winchester, Maureen Montrond, Keith Pietropaolo, Bruce Belanger, Courtney V Fletcher, Janet Hammond
doi:10.1101/2024.01.03.24300783
Bemnifosbuvir (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 target in vitro 90% effective concentration (EC 90 ) 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.
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