Population pharmacokinetics of molnupiravir in adults with COVID-19: Lack of clinically important exposure variation across individuals

Abstract

Effective antiviral treatments for coronavirus disease 2019 (COVID-19) are needed to reduce the morbidity and mortality associated with severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection, particularly in patients with risk factors for severe disease. Molnupiravir (MK-4482, EIDD-2801) is an orally administered, ribonucleoside prodrug of β-D-N4-hydroxycytidine (NHC) with submicromolar potency against SARS-CoV-2. A population pharmacokinetic (PopPK) analysis for molnupiravir exposure was conducted using 4202 NHC plasma concentrations collected in 1207 individuals from a phase I trial in healthy participants, a phase IIa trial in non-hospitalized participants with COVID-19, a phase II trial in hospitalized participants with COVID-19, and a phase II/III trial in non-hospitalized participants with COVID-19. Molnupiravir pharmacokinetics (PK) was best described by a two-compartment model with a transit-compartment absorption model and linear elimination. Molnupiravir apparent elimination clearance increased with body weight less-than-proportionally (power 0.412) and was estimated as 70.6 L/h in 80-kg individuals with a moderate interindividual variability (43.4% coefficient of variation). Additionally, effects of sex and body mass index on apparent central volume and food status and formulation on the absorption mean transit time were identified as statistically significant descriptors of variability in these PK parameters. However, none of the identified covariate effects caused clinically relevant changes in the area under the NHC concentration versus time curve between doses, the exposure metric most closely related to clinical response. Overall, the PopPK model indicates that molnupiravir can be administered in adults without dose adjustment based on age, sex, body size, food, and mild-to-moderate renal or mild hepatic impairment.

FIGURE 1

Schematic of the pharmacokinetic models for plasma NHC following molnupiravir administration used in (a) analysis stages 1 and 3 and (b) stage 2. CL/F, apparent elimination clearance; D1, duration of the zero‐order absorption process; k_a, first‐order absorption rate constant; MTT, mean absorption transit time; NHC, β‐D‐N4‐hydroxycytidine; Q/F, apparent distribution clearance; V_C/F, apparent central volume; V_P/F, apparent peripheral volume.

FIGURE 2

Visual predictive check plot for the final stage 3 pharmacokinetic model in participants with COVID‐19. Medians and percentiles are plotted at the median time for each interval of time relative to dose. CI, confidence interval; COVID‐19, coronavirus disease 2019; NHC, β‐D‐N4‐hydroxycytidine.

FIGURE 3

Forest plot of GMRs (90% CI) for stage 3 model‐predicted AUC_0–12 after molnupiravir 800 mg q12h. n is the number of participants in each group; [or] indicates respective end point is included in the interval; (or) indicates respective end point is not included in the interval. AUC_0–12, area under the NHC concentration versus time curve from 0 to 12 h postdose; CI, confidence interval; GMR, geometric mean ratio; NHC, β‐D‐N4‐hydroxycytidine; q12h, every 12 h.