GS-443902 and Pneumonia--Viral

Topics: Adenosine Triphosphate; Amodiaquine; Angiotensin-Converting Enzyme 2; Animals; Antiviral Agents; Betacoronavirus; Cats; Central Nervous System; Coronavirus Infections; Coronavirus, Feline; COVID-19; COVID-19 Drug Treatment; Feline Infectious Peritonitis; Humans; Nelfinavir; Pandemics; Peptidyl-Dipeptidase A; Pneumonia, Viral; Protease Inhibitors; Pyrrolidines; SARS-CoV-2; Sulfonic Acids

Remdesivir has received significant attention for its potential application in the treatment of COVID-19, caused by SARS-CoV-2. Remdesivir has already been tested for Ebola virus disease treatment and found to have activity against SARS and MERS coronaviruses. The remdesivir core contains GS-441524, which interferes with RNA-dependent RNA polymerases alone. In non-human primates, following IV administration, remdesivir is rapidly distributed into PBMCs and converted within 2 h to the active nucleoside triphosphate form, while GS-441524 is detectable in plasma for up to 24 h. Nevertheless, remdesivir pharmacokinetics and pharmacodynamics in humans are still unexplored, highlighting the need for a precise analytical method for remdesivir and GS-441524 quantification.. The validation of a reliable UHPLC-MS/MS method for remdesivir and GS-441524 quantification in human plasma.. Remdesivir and GS-441524 standards and quality controls were prepared in plasma from healthy donors. Sample preparation consisted of protein precipitation, followed by dilution and injection into the QSight 220 UHPLC-MS/MS system. Chromatographic separation was obtained through an Acquity HSS T3 1.8 μm, 2.1 × 50 mm column, with a gradient of water and acetonitrile with 0.05% formic acid. The method was validated using EMA and FDA guidelines.. Analyte stability has been evaluated and described in detail. The method successfully fulfilled the validation process and it was demonstrated that, when possible, sample thermal inactivation could be a good choice in order to improve biosafety.. This method represents a useful tool for studying remdesivir and GS-441524 clinical pharmacokinetics, particularly during the current COVID-19 outbreak.

Topics: Adenosine Monophosphate; Adenosine Triphosphate; Alanine; Betacoronavirus; Chromatography, High Pressure Liquid; Coronavirus Infections; COVID-19; COVID-19 Drug Treatment; Hemorrhagic Fever, Ebola; Humans; Pandemics; Pneumonia, Viral; SARS-CoV-2; Sensitivity and Specificity; Tandem Mass Spectrometry

Remdesivir is a prodrug of the nucleoside analogue GS-441524 and is under evaluation for treatment of SARS-CoV-2-infected patients.. To evaluate the pharmacokinetics of remdesivir and GS-441524 in plasma, bronchoalveolar aspirate (BAS) and CSF in two critically ill COVID-19 patients.. Remdesivir was administered at 200 mg loading dose on the first day followed by 12 days of 100 mg in two critically ill patients. Blood samples were collected immediately after (C0) and at 1 (C1) and 24 h (C24) after intravenous administration on day 3 until day 9. BAS samples were collected on Days 4, 7 and 9 from both patients while one CSF on Day 7 was obtained in one patient. Remdesivir and GS-441524 concentrations were measured in these samples using a validated UHPLC-MS/MS method.. We observed higher concentrations of remdesivir at C0 (6- to 7-fold higher than EC50 from in vitro studies) and a notable decay at C1. GS-441524 plasma concentrations reached a peak at C1 and persisted until the next administration. Higher concentrations of GS-441524 were observed in the patient with mild renal dysfunction. Mean BAS/plasma concentration ratios of GS-441524 were 2.3% and 6.4% in Patient 1 and Patient 2, respectively. The CSF concentration found in Patient 2 was 25.7% with respect to plasma. GS-441524 levels in lung and CNS suggest compartmental differences in drug exposure.. We report the first pharmacokinetic evaluation of remdesivir and GS-441524 in recovered COVID-19 patients. Further study of the pharmacokinetic profile of remdesivir, GS-441524 and the intracellular triphosphate form are required.

Topics: Adenosine Monophosphate; Adenosine Triphosphate; Aged; Alanine; Antiviral Agents; Betacoronavirus; Coronavirus Infections; COVID-19; Critical Illness; Female; Humans; Male; Pandemics; Pneumonia, Viral; Recovery of Function; SARS-CoV-2

Remdesivir was shown to inhibit RNA-dependent RNA-polymerases (RdRp) from distinct viral families such as from Filoviridae (Ebola) and Coronaviridae (SARS-CoV, SARS-CoV-2, MERS). In this study, we tested the ability of remdesivir to inhibit RdRps from the Flaviviridae family. Instead of remdesivir, we used the active species that is produced in cells from remdesivir, the appropriate triphosphate, which could be directly tested in vitro using recombinant flaviviral polymerases. Our results show that remdesivir can efficiently inhibit RdRps from viruses causing severe illnesses such as Yellow fever, West Nile fever, Japanese and Tick-borne encephalitis, Zika and Dengue. Taken together, this study demonstrates that remdesivir or its derivatives have the potential to become a broad-spectrum antiviral agent effective against many RNA viruses.

Topics: Adenosine Triphosphate; Antiviral Agents; Betacoronavirus; Coronavirus Infections; COVID-19; COVID-19 Drug Treatment; Flavivirus; Humans; Inhibitory Concentration 50; Pandemics; Pneumonia, Viral; RNA Viruses; RNA-Dependent RNA Polymerase; SARS-CoV-2