Development and Use of a Population Pharmacokinetic Model for Characterizing the Pharmacokinetics of Vonoprazan in Pediatric Patients

Gastroesophageal reflux disease affects about 20% of children. While proton pump inhibitors are a standard treatment, vonoprazan offers more rapid, potent, and prolonged gastric acid suppression in adults. Despite its promising pharmacological properties, vonoprazan is not yet approved for pediatric use. We aimed to develop and iteratively refine a population pharmacokinetic model to guide pediatric dosing for vonoprazan, characterize its pharmacokinetics in children and adolescents, and evaluate drug exposure across age groups. We developed a two-compartment linear pharmacokinetic model using data from eight adult (18-54 years) studies, one adolescent (≥ 12 to 17 years) study, and one study in children (≥ 6 to < 12 years). The model incorporated delayed absorption via three transit compartments parameterized by mean transit time, along with estimates for absorption rate constant and relative bioavailability. To capture variability, we quantified between-subject differences in clearance and central volume, accounting for correlation, and applied a combined additive and proportional error model to residual variability. Investigating relevant covariate effects allowed us to refine the model further. The model structure remained unchanged as pediatric data were added. The most significant parameter shifts occurred in the age effect on absorption rate and the weight effect on central volume. Predictions aligned closely with observed vonoprazan concentrations across age groups. Model-based simulations demonstrated consistent steady-state exposure among adults, adolescents, and children, with simulated pediatric doses aligning with the reference adult dose. In conclusion, the final two-compartment model successfully predicted vonoprazan pharmacokinetics and confirmed dose selection in children and adolescents aged 6 to 17 years.