Human Safety, Tolerability, and Pharmacokinetics of Molnupiravir, a Novel Broad-Spectrum Oral Antiviral Agent with Activity Against SARS-CoV-2.
Wendy P PainterWayne HolmanJim A BushFiras AlmazediHamzah MalikNicola C J E ErautMerribeth J MorinLaura J SzewczykGeorge R PainterPublished in: Antimicrobial agents and chemotherapy (2021)
Molnupiravir, EIDD-2801/MK-4482, the prodrug of the active antiviral ribonucleoside analog ß-d-N4-hydroxycytidine (NHC; EIDD-1931), has activity against a number of RNA viruses including severe acute respiratory syndrome coronavirus 2, severe acute respiratory syndrome coronavirus, Middle East respiratory syndrome coronavirus, and seasonal and pandemic influenza viruses.Single and multiple doses of molnupiravir were evaluated in this first-in-human, 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 hours, and declined with a geometric half-life of approximately 1 hour, with a slower elimination phase apparent following multiple doses or higher single doses (7.1 hours at the highest dose tested). Mean maximum observed concentration and area under the concentration versus time curve 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 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 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.
Keyphrases
- respiratory syndrome coronavirus
- sars cov
- double blind
- placebo controlled
- coronavirus disease
- endothelial cells
- clinical trial
- phase iii
- open label
- phase ii
- risk factors
- blood pressure
- study protocol
- pluripotent stem cells
- computed tomography
- randomized controlled trial
- air pollution
- induced pluripotent stem cells
- magnetic resonance
- drug delivery
- drug release
- risk assessment
- emergency department
- nucleic acid
- genetic diversity