Human Safety, Tolerability, and Pharmacokinetics of Molnupiravir, a Novel Broad-Spectrum Oral Antiviral Agent with Activity against SARS-CoV-2
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Open Access
- 30 April 2021
- journal article
- research article
- Published by American Society for Microbiology in Antimicrobial Agents and Chemotherapy
- Vol. 65 (5)
- https://doi.org/10.1128/AAC.02428-20
Abstract
Molnupiravir (EIDD-2801/MK-4482), the prodrug of the active antiviral ribonucleoside analog beta-D-N4-hydroxycytidine (NHC; EIDD-1931), has activity against a number of RNA viruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and seasonal and pandemic influenza viruses. Single and multiple doses of molnupiravir were evaluated in this first-inhuman, phase 1, randomized, double-blind, placebo-controlled study in healthy volunteers, which included evaluation of the effect of food on pharmacokinetics. EIDD-1931 appeared rapidly in plasma, with a median time of maximum observed concentration of 1.00 to 1.75 h, and declined with a geometric half-life of approximately 1 h, with a slower elimination phase apparent following multiple doses or higher single doses (7.1 h at the highest dose tested). Mean maximum observed concentration (C-max) and area under the plasma concentration versus time curve (AUC) increased in a dose-proportional manner, and there was no accumulation following multiple doses. When administered in a fed state, there was a decrease in the rate of absorption, but no decrease in overall exposure. Molnupiravir was well tolerated. Fewer than half of the subjects reported an adverse event, the incidence of adverse events was higher following administration of placebo, and 93.3% of adverse events were mild. One subject discontinued early due to rash. There were no serious adverse events, and there were no clinically significant findings in clinical laboratory, vital signs, or electrocardiography. Plasma exposures exceeded expected efficacious doses based on scaling from animal models; therefore, dose escalations were discontinued before a maximum tolerated dose was reached.This publication has 10 references indexed in Scilit:
- Therapeutically administered ribonucleoside analogue MK-4482/EIDD-2801 blocks SARS-CoV-2 transmission in ferretsNature Microbiology, 2020
- An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 in human airway epithelial cell cultures and multiple coronaviruses in miceScience Translational Medicine, 2020
- Small-Molecule Antiviral β- d - N 4 -Hydroxycytidine Inhibits a Proofreading-Intact Coronavirus with a High Genetic Barrier to ResistanceJournal of Virology, 2019
- Characterization of orally efficacious influenza drug with high resistance barrier in ferrets and human airway epitheliaScience Translational Medicine, 2019
- The prophylactic and therapeutic activity of a broadly active ribonucleoside analog in a murine model of intranasal venezuelan equine encephalitis virus infectionAntiviral Research, 2019
- An adipo-biliary-uridine axis that regulates energy homeostasisScience, 2017
- Metabolism of the Anti-Hepatitis C Virus Nucleoside β- d - N 4 -Hydroxycytidine in Different Liver CellsAntimicrobial Agents and Chemotherapy, 2004
- The crystal structures of severe acute respiratory syndrome virus main protease and its complex with an inhibitorProceedings of the National Academy of Sciences of the United States of America, 2003
- Tissue uridine pools: evidence in vivo of a concentrative mechanism for uridine uptake.1986
- Determination of serum and plasma uridine levels in mice, rats, and humans by high-pressure liquid chromatographyAnalytical Biochemistry, 1980