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  1. Article ; Online: First-in-human trial evaluating safety and pharmacokinetics of AT-752, a novel nucleotide prodrug with pan-serotype activity against dengue virus.

    Zhou, Xiao-Jian / Lickliter, Jason / Montrond, Maureen / Ishak, Laura / Pietropaolo, Keith / James, Dayle / Belanger, Bruce / Horga, Arantxa / Hammond, Janet

    Antimicrobial agents and chemotherapy

    2024  Volume 68, Issue 5, Page(s) e0161523

    Abstract: AT-752 is a novel guanosine nucleotide prodrug inhibitor of the dengue virus (DENV) polymerase with sub-micromolar, pan-serotype antiviral activity. This phase 1, double-blind, placebo-controlled, first-in-human study evaluated the safety, tolerability, ... ...

    Abstract AT-752 is a novel guanosine nucleotide prodrug inhibitor of the dengue virus (DENV) polymerase with sub-micromolar, pan-serotype antiviral activity. This phase 1, double-blind, placebo-controlled, first-in-human study evaluated the safety, tolerability, and pharmacokinetics of ascending single and multiple oral doses of AT-752 in healthy subjects. AT-752 was well tolerated when administered as a single dose up to 1,500 mg or when administered as multiple doses up to 750 mg three times daily (TID). No serious adverse events occurred, and the majority of treatment-emergent adverse events were mild in severity and resolved by the end of the study. In those receiving single ascending doses of AT-752, no pharmacokinetic sensitivity was observed in Asian subjects, and no food effect was observed. Plasma exposure of the guanosine nucleoside metabolite AT-273, the surrogate of the active triphosphate metabolite of the drug, increased with increasing dose levels of AT-752 and exhibited a long half-life of approximately 15-25 h. Administration of AT-752 750 mg TID led to a rapid increase in plasma levels of AT-273 exceeding the target
    MeSH term(s) Humans ; Antiviral Agents/pharmacokinetics ; Antiviral Agents/adverse effects ; Antiviral Agents/pharmacology ; Prodrugs/pharmacokinetics ; Prodrugs/pharmacology ; Prodrugs/adverse effects ; Dengue Virus/drug effects ; Male ; Adult ; Double-Blind Method ; Female ; Middle Aged ; Dengue/drug therapy ; Young Adult ; Half-Life ; Guanine Nucleotides
    Chemical Substances Antiviral Agents ; Prodrugs ; AT-752 ; Guanine Nucleotides
    Language English
    Publishing date 2024-03-25
    Publishing country United States
    Document type Journal Article ; Clinical Trial, Phase I ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
    ZDB-ID 217602-6
    ISSN 1098-6596 ; 0066-4804
    ISSN (online) 1098-6596
    ISSN 0066-4804
    DOI 10.1128/aac.01615-23
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 809: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)
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  2. Article ; Online: Human bronchopulmonary disposition and plasma pharmacokinetics of oral bemnifosbuvir (AT-527), an experimental guanosine nucleotide prodrug for COVID-19.

    Zhou, Xiao-Jian / Horga, Arantxa / Puri, Adeep / Winchester, Lee / Montrond, Maureen / Pietropaolo, Keith / Belanger, Bruce / Fletcher, Courtney V / Hammond, Janet

    The Journal of antimicrobial chemotherapy

    2024  

    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 ... ...

    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 825 mg for up to 3.5 days.
    Results: AT-511, the free base of bemnifosbuvir, was largely eliminated from the plasma within 6 h post dose in all dosing groups. Antiviral drug levels of bemnifosbuvir were consistently achieved in the lungs with bemnifosbuvir 550 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 0.62 µM at 4-5 h post dose. This exceeded the target in vitro 90% effective concentration (EC90) of 0.5 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 550 mg bemnifosbuvir twice daily currently under further clinical evaluation in persons with COVID-19.
    Language English
    Publishing date 2024-05-06
    Publishing country England
    Document type Journal Article
    ZDB-ID 191709-2
    ISSN 1460-2091 ; 0305-7453
    ISSN (online) 1460-2091
    ISSN 0305-7453
    DOI 10.1093/jac/dkae122
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 1197: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)
    Zs.MO 124: Show issues

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  3. Article ; Online: Human bronchopulmonary disposition and plasma pharmacokinetics of oral bemnifosbuvir (AT-527), an experimental guanosine nucleotide prodrug for COVID-19

    Zhou, Xiao-Jian / Horga, Arantxa / Puri, Adeep / Winchester, Lee / Montrond, Maureen / Pietropaolo, Keith / Belanger, Bruce / Fletcher, Courtney V. / Hammond, Janet

    medRxiv

    Abstract: 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 ... ...

    Abstract 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 (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.
    Keywords covid19
    Language English
    Publishing date 2024-01-08
    Publisher Cold Spring Harbor Laboratory Press
    Document type Article ; Online
    DOI 10.1101/2024.01.03.24300783
    Database COVID19

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