Population Pharmacokinetic Modeling Practice of Time‐Varying Clearance: Insights from a First‐in‐Human Study Case

Accurate characterization of time-varying clearance (CL) is critical during early drug development, as it informs clinical study design and dosing strategies for future trials. However, detecting and modeling time-varying clearance is challenging due to limited data availability in early clinical development. Using pharmacokinetic data from a well-controlled first-in-human (FIH) study with single and multiple ascending doses, this study explored time-varying clearance, dose proportionality, and meal effects on pharmacokinetics (PK) of utreloxastat. Initial data analysis revealed time-varying systemic clearance, more-than-dose-proportional kinetics, and meal-dependent PK alterations, which informed the development of a population pharmacokinetic (PopPK) model. A systematic evaluation of twelve distinct time-varying clearance models identified an exponential time-varying clearance model within a two-compartment framework, incorporating first-order absorption with eight transit compartments, as the best fit to the data. Covariate analysis confirmed that sex, age, and body weight were not significant predictors of variability. This study is the first to showcase a comparative evaluation of time-varying clearance for a small molecule. It highlights the innovative application of time-varying clearance modeling during the FIH study as a pivotal step in optimizing model-informed dosing strategies. This approach underscores its importance in addressing non-linear pharmacokinetics and enhancing drug development practices for future clinical trials.