Population Pharmacokinetics and Exposure–Response Analysis of Oral Pixavir Marboxil in Adults and Adolescents with Influenza

Background/Objectives: Pixavir marboxil is a novel oral cap-dependent endonuclease inhibitor that is rapidly converted to its active metabolite pixavir. This study aimed to characterize the population pharmacokinetics (PopPK) of pixavir, identify clinical covariates affecting its pharmacokinetics, and evaluate the exposure–response relationship to inform optimal dosing in the treatment of acute influenza. Methods: Data were pooled from three clinical studies spanning Phase I to Phase III trials and included adults and adolescents aged ≥12 years. PopPK modeling was conducted using NONMEM software. Individual exposure metrics, including the 24-h post-dose concentration, maximum concentration, and area under the concentration-time curve from time zero to infinity, were derived using Bayesian estimation based on the final PopPK model. Efficacy endpoints included time to alleviation of influenza-related symptoms and changes in viral titer and viral RNA load from baseline to Day 2. Safety was evaluated through the incidence of treatment-related adverse events. Results: Pixavir pharmacokinetics were best described by a two-compartment model. Body weight significantly influenced clearance and central volume of distribution, while dose amount had a notable effect on bioavailability. Food, sex and age had no clinically meaningful impact on pharmacokinetics. Exposure–response analysis showed no clear relationship between pixavir exposure and both efficacy and safety endpoints within the studied dosing range. Conclusions: The weight-based dosing regimen of pixavir marboxil (40 mg for <80 kg and 80 mg for ≥80 kg) is supported, as it reduces body-weight-driven exposure variability and maintains exposure within the clinically characterized range in adults and adolescents with acute influenza.