Population Pharmacokinetics of Rabeprazole and Dosing Recommendations for the Treatment of Gastroesophageal Reflux Disease in Children Aged 1–11 Years

Background and Objective Rabeprazole sodium is a proton pump inhibitor used for the treatment of gastroesophageal reflux disease (GERD). The objective of this study was to develop a population pharmacokinetic model for rabeprazole that describes concentration–time data arising from phase I and phase III studies in adult and pediatric subjects, including neonates and preterm infants, and propose dosing recommendations for pediatric subjects aged 1–11 years. Methods A total of 4,417 pharmacokinetic observations from 597 subjects aged 6 days to 55.7 years with body weights of 1.15–100 kg were used to develop the population pharmacokinetic model using non-linear mixed-effects modeling techniques. Weight and age were included in the structural model to describe clearance (CL) and central volume of distribution ( V c ). Other covariates considered during model development included sex, race, creatinine clearance, hepatic function, formulation, feeding status, and route of administration. The final model was used to determine doses for pediatric subjects aged 1–11 years to achieve a steady-state area under the plasma concentration–time curve across the dose interval of 24 h (AUC 24 ) within the target adult AUC 24 range obtained following a rabeprazole 10 mg dose. Results The best model was a two-compartment disposition model with a sequential zero-order duration of input (Dur), first-order absorption ( k a ) following a lag time ( T lag ), with weight and age effects on CL and V c . Formulation type and feeding status described some of the variability in bioavailability and the absorption parameters T lag , Dur, and k a . A dosage regimen of 5 mg once daily for children <15 kg, and 10 mg for children ≥15 kg is recommended for 1- to 11-year-old pediatric patients with GERD. Conclusions The pharmacokinetics of rabeprazole were described with good precision following administration of rabeprazole across a range of doses and in a range of formulations.