Sarah McLeay (1), Bruce Green (1), William Treem (2), An Thyssen (3), Eric Mannaert (3), Holly Kimko (2)
(1) Model Answers Pty Ltd, Brisbane, Queensland, Australia, (2) Janssen Research & Development, LLC, Raritan, New Jersey, USA, (3) Janssen Research & Development, LLC, Turnhout, Belgium
Objectives: To develop a population PK model for rabeprazole that describes concentration-time data arising from Phase 1 and Phase 3 studies in adult and pediatric subjects, including neonates and preterm infants, and propose dosing recommendations for pediatric subjects aged 1-11 years for the treatment of gastroesophageal reflux disease (GERD).
Methods: A total of 4417 PK 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 PK model using nonlinear mixed effects modeling techniques. Weight and age were included in the structural model to describe clearance (CL) and central volume of distribution (Vc). 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 AUCs within the target adult AUC range obtained following a 10 mg rabeprazole dose.
Results: The best model to fit the data was a 2-compartment disposition model with a sequential zero-order (D1), first-order (KA) absorption following a lag time (ALAG), with weight and age effects on CL and Vc. Formulation type and feeding status described some of the variability in bioavailability and the absorption parameters ALAG, D1, and KA. A dosage regimen of 5 mg once daily for children < 15 kg, and 10 mg for children ≥ 15 kg is recommended for 1-11 year old pediatric patients with GERD.
Conclusions: The model described the PK of rabeprazole with good precision following administration of rabeprazole across a range of doses and in a range of formulations.
Reference: PAGE 22 (2013) Abstr 2811 [www.page-meeting.org/?abstract=2811]
Poster: Paediatrics