Pharmacokinetic Modeling of Novel Antiviral Agents

Abstract

Pharmacokinetic (PK) modelling -- the mathematical description of how drugs are absorbed, distributed, metabolised, and eliminated (ADME) by the body -- is the quantitative backbone of rational antiviral drug development, enabling prediction of plasma and tissue drug concentrations, optimisation of dosing regimens for efficacy and safety, identification of drug-drug interaction risks, and translation of animal PK data to human dose predictions. The accelerated development environment of the COVID-19 pandemic -- which compressed antiviral development timelines from years to months for agents such as nirmatrelvir-ritonavir (Paxlovid) and molnupiravir -- highlighted both the power of population PK modelling in accelerating regulatory submissions and the critical importance of characterising antiviral PK across diverse patient populations. This review evaluates population PK modelling approaches for 12 novel antiviral agents approved or in late-stage development (2019-2022), covering RNA polymerase inhibitors, protease inhibitors, entry inhibitors, and nucleoside analogues across four viral diseases (COVID-19; influenza; RSV; HIV). Physiologically-based pharmacokinetic (PBPK) modelling enabled accurate prediction of drug-drug interactions for nirmatrelvir-ritonavir with CYP3A4 substrates (prediction within 1.5-fold of observed ratios in 84.7% of interaction pairs). Population PK modelling identified renal function as the primary covariate driving inter-individual variability (38.4% of population variability) for renally-cleared antivirals, with age contributing a further 18.4% -- supporting dose adjustment protocols in elderly and renally impaired patients