Human Safety, Tolerability, & Pharmacokinetics of a Novel Broad-Spectrum Oral Antiviral Compound, Molnupiravir, with Activity Against SARS-CoV-2

Molnupiravir, EIDD-2801/MK-4482, the prodrug of the ribonucleoside analog ß-d-N4-hydroxycytidine (NHC), has shown activity against numerous RNA viruses including severe acute respiratory syndrome coronavirus 2, severe acute respiratory syndrome coronavirus etc.

A first-in-human, phase 1, randomized, double-blind, placebo-controlled study investigated single and multiple doses of molnupiravir in healthy volunteers, along with assessing the effect of food on pharmacokinetics.

EIDD-1931 was rapidly observed in plasma, with 1.00 to 1.75 hours of median time of maximum concentration, reaching its geometric half-life in nearly 1 hour. Further it demonstrated slower elimination phase (7.1 hours at the highest tested dose) after multiple doses or higher single doses. 

Mean maximum observed concentration and area under the concentration against time curve increased dose-proportionally, and no accumulation was observed after multiple doses. When given in a fed state, a decrease in the rate of absorption was observed but not in overall exposure.

Molnupiravir showed good tolerability. Adverse event were reported less in molnupiravir group (<50%) than the placebo group. Furthermore, 93.3% of adverse events were mild. A participant dropped off from the study after appearance of rash. No serious adverse events, clinically significant findings in clinical laboratory, vital signs, or electrocardiography were noted. Plasma exposures surpassed expected efficacious doses founded on scaling from animal models; thus, dose escalations were terminated before reaching a maximum tolerated dose.

SOURCE- Painter WP, Holman W, Bush JA, Almazedi F, Malik H, Eraut NCJE, Morin MJ, Szewczyk LJ, Painter GR. medRxiv 2020.12.10.20235747; doi: https://doi.org/10.1101/2020.12.10.20235747