[Objective]
Molnupiravir (MOV) is a prodrug of the ribonucleoside analog, N-hydroxycytidine (NHC), that inhibits replication of RNA viruses including SARS-CoV-2 and is the first approved oral COVID-19 therapy for emergency use in Japan. In this study, safety and pharmacokinetics (PK) following single (SD) and multiple oral dose administration (MD) of MOV capsule formulation were assessed. This work focuses on the PK results in this study, including food effect at the therapeutic dose level of 800 mg.
[Method]
This was a 2-part (SD and MD parts), randomized, placebo-controlled, double-blind study conducted in Japanese healthy participants. In Part 1 (SD), doses of 200, 400, 800 and 1600 mg in the fasted state along with 800 mg in the fed state were evaluated. In Part 2 (MD), doses of 400 and 800 mg every 12 hours (Q12H) for 5.5 day were evaluated. Blood was collected to quantify the concentration of NHC in plasma and NHC triphosphate (NHC-TP), the active metabolite of NHC, in peripheral blood mononuclear cells. PK parameter values were determined by employing a noncompartmental approach in Phoenix WinNonlin^TM.
[Result and Discussion]
NHC appeared rapidly in plasma following administration of MOV in the fasted state, with median Tmax between 1.0 and 2.0 hours. AUC and Cmax of plasma NHC increased approximately dose proportionally after SD of MOV 200 to 1600 mg. Following MD Q12H, the effective half-life of NHC was 2 to 3 hours and limited accumulation ratios of 1.03 and 1.05 were observed for AUC0-12 at MOV 400 and 800 mg, respectively. The PK of NHC-TP also demonstrated roughly dose proportional PK. Following administration of MOV 800 mg with a high-fat meal, only a modest reduction (24%) in plasma NHC Cmax with comparable AUC was observed.
[Conclusion]
These PK results in this study supported the therapeutic dosage of 800 mg every 12 hours in Japanese for the treatment of mild to moderate COVID-19. These results also indicated that MOV can be taken without regard to food.