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. 2021 May 1;65(5):e02428-20.
doi: 10.1128/AAC.02428-20. Epub 2021 Mar 1.

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

Wendy P Painter  1 , Wayne Holman  1 , Jim A Bush  2 , Firas Almazedi  2 , Hamzah Malik  2 , Nicola C J E Eraut  2 , Merribeth J Morin  1 , Laura J Szewczyk  1 , George R Painter  3
Affiliations

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

Wendy P Painter et al. Antimicrob Agents Chemother. .

Abstract

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.

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Figures

FIG 1
FIG 1
Molnupiravir is rapidly converted in the plasma to EIDD-1931 (NHC), which after distribution into various tissues is converted by host kinases into EIDD-1931 5′-triphosphate, the active antiviral agent.
FIG 2
FIG 2
Arithmetic mean plasma concentrations of EIDD-1931 (50 to 1,600 mg molnupiravir, single ascending doses).
FIG 3
FIG 3
Arithmetic mean plasma concentrations of EIDD-1931 (50 to 800 mg molnupiravir, twice-daily multiple ascending doses) on day 1 (top) and day 6 (bottom).
FIG 4
FIG 4
Arithmetic mean plasma concentration of EIDD-1931 (food effect).
See this image and copyright information in PMC

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