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

• Authors: Sébastien Bihorel, Simulation Plus; Youfang Cao, Merck & Co., Inc.; Akshita Chawla, Merck & Co., Inc.; Ruthie Birger, Merck & Co., Inc.; Brian M. Maas, Merck & Co., Inc.; Wei Gao, Merck & Co., Inc.; Stefan Roepcke, Simulation Plus; Susanne Sardella, Simulation Plus; Rebecca HUmphrey, Simulation Plus; Sindhuri Kondragunta, Simulation Plus; Bhuvana Jayaraman, Simulation Plus; Monika Martinho, Merck & Co., Inc.; Wendy Painter, Ridgeback Biotherapeutics; George R. Painter, Emory University; Wayne Holman, Ridgeback Biotehrapeutics; Carisa De Anda, Merck & Co., Inc.; Michelle L. Brown, Merck & Co., Inc.; Matthew G. Johnson, Merck & Co., Inc.; Amanda Paschke, Merck & Co., Inc.; Matthew L. Rizk, Merck & Co., Inc.; Julie A. Stone, Merck & Co., Inc.
• Journal Title: CPT: Pharmacometrics and Systems Pharmacology
• Volume: Volume 12, Number 12
• Publisher: Wiley Periodicals LLC | 2023-10-05, Pages 1859-1871
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1002/psp4.13031
• Subjects: Health Sciences, Pharmacology; Health Sciences, Public Health
• Keywords: COVID‐19; antiviral treatments; SARS‐CoV‐2; Pharmacokinetics; Infectious Diseases

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.