Model-Based Virtual Clinical Trial Reveals Renal Impairment and Body Size as Key Determinants of Pharmacokinetic Variability and Drug-Drug Interaction Risk in Propranolol Therapy

Background/Objectives: Propranolol (PROP) is a non-selective β-blocker widely prescribed for cardiovascular and neurological disorders. Its pharmacokinetics (PK) are highly variable, and co-administration with omeprazole (OME), a CYP2C19 substrate and inhibitor, may alter systemic exposure. Herein, this study aimed to investigate factors influencing PROP PK variability and evaluate the effect of OME coadministration using physiologically based pharmacokinetic (PBPK) modeling and population PK (popPK) analysis. Methods: PBPK models for PROP and OME were developed and validated against published data. DDI simulations were conducted across clinically relevant dosing regimens. A two-period fixed-sequence virtual trial of 125 subjects was simulated with PROP alone and PROP combined with OME. Population PK (popPK) analysis was performed on simulated plasma concentration data to identify covariates affecting PROP disposition and quantify DDI magnitude. Results: PBPK models were successfully developed and validated. PROP disposition was best described by a two-compartment model with linear elimination. Health status was found to influence clearance, and body surface area (BSA) affected the central volume of distribution. Co-administration with OME increased PROP exposure, with larger effects in patients with renal impairment. Simulated plasma concentrations remained below established toxicity thresholds. Conclusions: Virtual clinical trials integrating PBPK and popPK modeling provide a robust approach to identifying key determinants of PK variability and DDI risk. Although these findings were not directly translated to clinical observations, this helps identify sources of PK variability in PROP treatment settings and factors that may intensify its interaction with OME, thereby supporting model-informed precision dosing to enhance safety and efficacy.