ABSTRACT
Background: Bemnifosbuvir (BEM, AT-527) is a guanosine nucleotide prodrug in development for the treatment of COVID-19 and chronic HCV. BEM was identified in vitro as an inhibitor [competitive and time-dependent inhibition (TDI)] and inducer of CYP3A4, prompting evaluation of the clinical relevance of these results in a Ph 1 drug-drug interaction (DDI) study in healthy participants using midazolam (MDZ), a sensitive CYP3A4 substrate as an index drug. Method(s): Two groups of 12 healthy participants were enrolled and received a single dose of 2mg MDZ alone on Day 1. Between Days 3 and 7 inclusive, all participants received oral BEM 550mg twice daily (BID). On day 3 and day 7, Group A received a single dose of 2mg MDZ simultaneously with BEM;Group B on these two days received 2mg MDZ 2h after BEM. Serial plasma samples were obtained and measured for MDZ and 1-OH-MDZ levels. Result(s): A single dose (simultaneous or staggered) of BEM slightly increased the plasma exposure of MDZ (14%-26%). Staggered BEM had less impact (8%-17%) on 1-OH-MDZ than simultaneous dosing (22%-31%). Inhibitory effect of BEM was more pronounced with repeat dosing, consistent with in vitro data showing TDI on CYP3A4. After repeat dosing, simultaneously administered BEM increased plasma MDZ exposure by 83%-98%, without affecting the exposure of 1-OH-MDZ. With repeat dosing, staggered BEM showed less effect on both MDZ and 1-OH-MDZ. There was no effect on vital signs, ECG, and no SAEs or drug discontinuations. Conclusion(s): BEM is a weak inhibitor (ratio between 1.25 and 2) of CYP3A4. No dose adjustment is needed for drugs that are substrates of CYP3A4 when co-administered with BEM.
ABSTRACT
Background: Bemnifosbuvir (BEM, AT-527) is a guanosine nucleotide prodrug candidate for the treatment of COVID-19 and chronic HCV. BEM was identified in vitro as an inhibitor of drug transporters P-glycoprotein, breast cancer resistant protein (BCRP) and organic anion transporting polypeptide 1B1 (OATP1B1). Ph 1 studies in healthy participants were conducted to assess the clinical implications of these results using digoxin (DIG) and rosuvastatin (ROSU) as P-gp and BCRP/ OATP1B1 index drugs, respectively. Method(s): Both studies employed a similar design with 2 groups of 14 healthy participants: Day 1/period 1, all participants received a single dose of DIG 0.25mg or ROSU 10mg alone. In period 2, participants received DIG 0.25mg or ROSU 10mg with BEM 1100mg, simultaneously (n=14) or staggered by 2h (n=14). Serial plasma samples were collected and quantitated for DIG or ROSU concentrations. Result(s): A single dose of BEM 1100mg simultaneously administered slightly increased the Cmax of DIG (78%), yet had no effect on its AUC, consistent with the transient nature of BEM plasma PK. When dosed staggered, BEM did not affect the PK of DIG. A single dose (simultaneous or staggered) of BEM 1100mg slightly increased the plasma exposure of ROSU (20%-40%). There was no effect on vital signs, ECG, and no SAEs or drug discontinuations. Conclusion(s): A single high dose of BEM 1100mg only slightly increased the plasma exposure of the P-gp and BCRP/OATP1B1 index drugs DIG and ROSU. BEM has low potential to exhibit clinical meaningful inhibition of these transporters. No dose adjustment will be needed for drugs that are sensitive substrates of P-gp or BCRP/OAT1B1 when co-administered with BEM, staggered dosing may lessen any DDI risk.
ABSTRACT
Xinguan No. 3 has been recommended for the treatment of coronavirus disease 2019 (COVID-19);however, its potential mechanisms are unclear. This study aims to explore the mechanisms of Xinguan No. 3 against COVID-19 through network pharmacology and molecular docking. We first searched the ingredients of Xinguan No. 3 in three databases (Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform, Traditional Chinese Medicines Integrated Database, and The Encyclopedia of Traditional Chinese Medicine). The active components and their potential targets were predicted through the SwissTargetPrediction website. The targets of COVID-19 can be found on the GeneCards website. Protein interaction analysis, screening of key targets, functional enrichment of key target genes, and signaling pathway analysis were performed through Search Tool for the Retrieval of Interacting Genes databases, Metascape databases, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway databases. Finally, the affinity of the key active components with the core targets was verified by molecular docking. The results showed that five core targets had been screened, including MAPK1, NF-kappa B1, RELA, AKT1, and MAPK14. Gene ontology enrichment analysis revealed that the key targets were associated with inflammatory responses and responses to external stimuli. KEGG enrichment analysis indicated that the main pathways were influenza A, hepatitis B, Toll-like receptor signaling pathway, NOD-like receptor signaling pathway, and TNF signaling pathway. Therefore, Xinguan No. 3 might play a role in treating COVID-19 through anti-inflammatory, immune responses, and regulatory responses to external stimuli.
ABSTRACT
Chronic pain produces the largest non-fatal burden of disease, yet our understanding of factors that contribute to the transition from acute chronic pain are poorly understood. The Acute to Chronic Pain Signatures Program (A2CPS) is a longitudinal, multi-site observational study to identify biomarkers (individual or biosignature combinations) that predict susceptibility or resilience to the development of chronic pain after surgery (knee replacement or thoracotomy). Due to the COVID-19 pandemic, however, travel between sites was restricted just as the study was preparing to begin enrollment. Here, we present multiple training protocol adaptations that were successfully implemented to facilitate remote research-related training. The A2CPS consortium includes 2 Multisite Clinical Centers (MCCs, 10 recruitment sites), a Clinical Coordinating Center (CCC), a Data Integration and Resource Center (DIRC), 3 Omics Data Generation Centers, and representation from the NIH Pain Consortium, Common Fund, and National Institute of Drug Abuse. The A2CPS is collecting candidate and exploratory biomarkers including pain, fatigue, function, sleep, psychosocial factors, quantitative sensory testing (QST), genomics, proteomics, metabolomics, lipidomics, and brain imaging. The CCC adapted the A2CPS training and evaluation techniques for certifying the MCCs to ensure competency with recruitment, assessments (surveys, QST, function), and data entry across clinical sites using a combination of virtual training sessions, standardized quantitative measurements, video demonstrations, and reliability assessments. Staff at data collection sites have been successfully certified in all psychophysical assessments (QST, function). This included use of stop watches and metronomes to ensure standard application rates, completion of application-rate and inter-rater-reliability worksheets at each clinical site, designation of site-specific master examiners, training rubrics and video demonstration to verify competency was harmonized across sites. Adaptation of training protocols to a remote format enabled initiation of subject enrollment while maintaining documented standards with high data completion rates for surveys and assessments. The A2CPS Consortium is supported by the National Institutes of Health Common Fund, which is managed by the OD/Office of Strategic Coordination (OSC). Consortium components include: Clinical Coordinating Center (UO1NS077179), Data Integration and Resource Center (UO1NS077352), Omics Data Generation Centers (U54DA049116, U54DA049115, U54DA09113), and Multisite Clinical Centers: MCC 1 (UM1NS112874) and MCC 2 (UM1NS118922). Postdoctoral support for GB provided by the National Institutes of Neurological Disease and Stroke (NINDS) of the NIH under Award Number U24NS112873-03S2.
ABSTRACT
Background: AT-527 is a guanosine nucleotide prodrug with potent in vitro antiviral activity against flaviviruses and coronaviruses including SARS-CoV-2 (EC90=0.5 μM), the virus responsible for COVID-19. AT-527 exhibits a unique mechanism of action predominantly targeting the NiRAN function of the SARS-CoV-2 polymerase. The clinical safety to date and in vitro potency of AT-527 prompted evaluation of this drug candidate in patients with COVID-19. The purpose of this study was to assess the safety and pharmacokinetics (PK) of AT-527 dosed 550 mg twice a day (BID) in healthy subjects and to predict human lung exposure of the active triphosphate metabolite AT-9010. Methods: Twenty healthy subjects were randomized 1:1 to receive orally AT-527 550 mg BID or matching placebo for 5 days. Safety assessments included adverse events (AEs), vital signs, electrocardiograms (ECGs) and standard safety laboratory tests. Intensive PK sampling was performed after the first and last two doses and assayed for plasma AT-511, the free base form, and metabolites including AT-273, the guanosine nucleoside metabolite, a surrogate for intracellular AT-9010. Results: AT-527 was well tolerated with no discontinuations, serious AEs, clinically significant changes in vital signs or ECGs based on still blinded safety data. AT-511 was rapidly absorbed followed by fast and extensive metabolic conversion to an L-alanyl intermediate metabolite AT-551 and ultimately intracellular AT-9010, reflected by plasma AT-273. Steady state levels were quickly achieved by the third dose of AT-527. Plasma levels of AT-273 were used to predict lung concentrations of AT-9010 using a scaling factor of 1.2X previously determined from in vivo tissue distribution of the triphosphate metabolite in cynomolgus monkeys. As early as 3 hours after the first dose and maintained from the second dose throughout 5 days of dosing, the predicted lung AT-9010 levels were consistently above the EC90 of the drug candidate in inhibiting SARS-CoV-2 replication in vitro. Conclusion: AT-527 orally administered with a regimen of 550 mg BID for 5 days was well-tolerated in healthy subjects. A favorable PK profile was demonstrated: rapid attainment of steady state with a fast build-up of trough levels of AT-273, which were reflective of efficacious active triphosphate metabolite levels in the lungs. AT-527, with a 550 mg BID dosing regimen, is currently being evaluated in Phase 2 clinical studies as an early treatment option for COVID-19.