Abstract
Onradivir (ZSP1273) is a novel antiviral agent with broad-spectrum activity, favorable pharmacokinetics, and potential for treating influenza virus infections. This study developed a population pharmacokinetic model to evaluate the impact of factors on onradivir pharmacokinetics, explore exposure-efficacy and exposure-safety relationships, and inform pediatric dose selection in clinical trial. Six clinical trial datasets were pooled for population pharmacokinetic analysis. Covariates were subsequently screened. The impact of significant covariates on exposure was assessed through simulation. Safety and efficacy endpoints were defined as the incidence rate of adverse events and the average viral load (baseline-adjusted) over T, respectively. Binary endpoints were analyzed using logistic regression and continuous endpoints using scatter plots and the sigmoid Emax model. Pediatric dosing was determined through allometric scaling and simulations referencing adult exposure. Significant covariates included weight, health status, sex, and formulation process, but their impact on exposure did not warrant dose adjustments. Diarrhea was the main mild and transient side effect. Antiviral modeling suggested a flat or saturated exposure-response relationship within the studied exposure window. Proposed pediatric dosing regimens for clinical trial evaluation are 600 mg once daily (>40 kg), 400 mg once daily (20-40 kg), and 200 mg once daily (10-20 kg). This analysis provides a preliminary basis for onradivir dose selection in pediatric clinical trials, indicating possible directions for dose adjustment and informing future research and development efforts. SIGNIFICANCE STATEMENT: This study establishes the first population pharmacokinetic model for onradivir, identifying weight, health status, and sex as key covariates without necessitating dose adjustments. It provides weight-based pediatric dosing suggestions (200-600 mg once daily) in a pediatric clinical trial.