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

Abstract

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 phaseI and phaseIII studies in adult and pediatric subjects, including neonates and preterm infants, and propose dosing recommendations for pediatric subjects aged 1-11years. A total of 4,417 pharmacokinetic observations from 597 subjects aged 6days to 55.7years with body weights of 1.15-100kg 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 1-11years to achieve a steady-state area under the plasma concentration-time curve across the dose interval of 24h (AUC24) within the target adult AUC24 range obtained following a rabeprazole 10mg dose. 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 5mg once daily for children <15kg, and 10mg for children ≥15kg is recommended for 1- to 11-year-old pediatric patients with GERD. The pharmacokinetics of rabeprazole were described with good precision following administration of rabeprazole across a range of doses and in a range of formulations.