Human bronchopulmonary disposition and plasma pharmacokinetics of oral bemnifosbuvir (AT-527), an experimental guanosine nucleotide prodrug for COVID-19.
J Antimicrob Chemother
; 79(6): 1423-1431, 2024 06 03.
Article
en En
| MEDLINE
| ID: mdl-38708557
ABSTRACT
BACKGROUND:
Bemnifosbuvir (AT-527) is a novel oral guanosine nucleotide antiviral drug for the treatment of persons 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.OBJECTIVES:
This Phase 1 study in healthy subjects aimed to assess the bronchopulmonary pharmacokinetics, safety and tolerability of repeated doses of bemnifosbuvir.METHODS:
A total of 24 subjects were assigned to receive bemnifosbuvir twice daily at doses of 275, 550 or 825â mg for up to 3.5â days.RESULTS:
AT-511, the free base of bemnifosbuvir, was largely eliminated from the plasma within 6â h post dose in all dosing groups. Antiviral drug levels of bemnifosbuvir were consistently achieved in the lungs with bemnifosbuvir 550â mg twice daily. 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 0.62â µM at 4-5â h post dose. This exceeded the target in vitro 90% effective concentration (EC90) of 0.5â µM for antiviral drug exposure against SARS-CoV-2 replication in human airway epithelial cells. Bemnifosbuvir was well tolerated across all doses tested, and most treatment-emergent adverse events reported were mild in severity and resolved.CONCLUSIONS:
The favourable pharmacokinetics and safety profile of bemnifosbuvir demonstrates its potential as an oral antiviral treatment for COVID-19, with 550â mg bemnifosbuvir twice daily currently under further clinical evaluation in persons with COVID-19.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Antivirales
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Profármacos
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SARS-CoV-2
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Tratamiento Farmacológico de COVID-19
Límite:
Adult
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Año:
2024
Tipo del documento:
Article