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

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 ß-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.

Informatics: the fuel for pharmacometric analysis.

The current informal practice of pharmacometrics as a combination art and science makes it hard to appreciate the role that informatics can and should play in the future of the discipline and to comprehend the gaps that exist because of its absence. The development of pharmacometric informatics has important implications for expediting decision making and for improving the reliability of decisions made in model-based development. We argue that well-defined informatics for pharmacometrics can lead to much needed improvements in the efficiency, effectiveness, and reliability of the pharmacometrics process. The purpose of this paper is to provide a description of the pervasive yet often poorly appreciated role of informatics in improving the process of data assembly, a critical task in the delivery of pharmacometric analysis results. First, we provide a brief description of the pharmacometric analysis process. Second, we describe the business processes required to create analysis-ready data sets for the pharmacometrician. Third, we describe selected informatic elements required to support the pharmacometrics and data assembly processes. Finally, we offer specific suggestions for performing a systematic analysis of existing challenges as an approach to defining the next generation of pharmacometric informatics.