Leveraging Omeprazole PBPK/PD Modeling to Inform Drug-Drug Interactions and Specific Recommendations for Pediatric Labeling.

Background/Objectives: Omeprazole is widely used for managing gastrointestinal disorders like GERD, ulcers, and H. pylori infections. However, its use in pediatrics presents challenges due to drug interactions (DDIs), metabolic variability, and safety concerns. Omeprazole's pharmacokinetics (PK), primarily influenced by CYP2C19 metabolism, is affected by ontogenetic changes in enzyme expression, complicating dosing in children. Methods: This study aimed to develop and validate a physiologically based pharmacokinetic (PBPK) model for omeprazole and its metabolites to predict age-related variations in metabolism and response. Results: The PBPK model successfully predicted exposure to parent and metabolites in adults and pediatrics, incorporating competitive and mechanism-based inhibition of CYP2C19 and CYP3A4 by omeprazole and its metabolites. By accounting for age-dependent metabolic pathways, the model enabled priori predictions of omeprazole exposure in different age groups. Linking PK to the pharmacodynamics (PD) model, we described the impact of age-related physiological changes on intragastric pH, the primary outcome for proton pump inhibitors efficacy. Conclusions: The PBPK-PD model allowed for the virtual testing of dosing scenarios, providing an alternative to clinical studies in pediatrics where traditional DDI studies are challenging. This approach offers valuable insights for accurate dosing recommendations in pediatrics, accounting for age-dependent variability in metabolism, and underscores the potential of PBPK modeling in guiding pediatric drug development.