Assessment of Pharmacokinetics, Safety, and Tolerability Following Twice-Daily Administration of Molnupiravir for 10 Days in Healthy Participants.

Molnupiravir is an orally administered, small-molecule ribonucleoside prodrug of β-D-N4-hydroxycytidine (NHC), which has demonstrated potent, broad-spectrum preclinical activity against RNA viruses and has a high barrier to the development of resistance. A double-blind, placebo-controlled, phase I trial was conducted to evaluate the pharmacokinetics (PK), safety, and tolerability of 10.5-day administration of multiple doses of molnupiravir and its metabolites in healthy, adult participants. Participants were randomly assigned (3:1) to receive molnupiravir (400 mg [n = 6], 600 mg [n = 6], and 800 mg [n = 12]) or matching placebo (n = 8) every 12 h (Q12H) for 10.5 days. Blood was collected to evaluate the PK of NHC in plasma and of its active metabolite, NHC-triphosphate (NHC-TP), in peripheral blood mononuclear cells (PBMCs). Molnupiravir was generally well tolerated. All adverse events were mild or moderate in severity and none led to treatment discontinuation. No clinically meaningful dose-related safety findings were observed. Mean time to maximal concentration was ~1.50 to 1.98 h for plasma NHC and ~4.00 to 8.06 h for PBMC NHC-TP. Accumulation was minimal (<1.2) for NHC and ~2 to 2.5-fold for NHC-TP. Plasma NHC PK was generally dose proportional, and PBMC NHC-TP PK was less than dose proportional over the dose range studied. NHC and NHC-TP PK support twice-daily administration. Overall, molnupiravir administered at up to 800 mg Q12H for 10.5 days was generally well tolerated in healthy participants, with dose-linear PK, supporting the evaluation of longer molnupiravir dosing up to 10 days in future clinical trials.