Population Pharmacokinetics of Rabeprazole and Dosing Recommendations for the Treatment of Gastroesophageal Reflux Disease in Children Aged 1–11 Years
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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.
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 (AUC24) within the target adult AUC24 range obtained following a rabeprazole 10 mg 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 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.
The pharmacokinetics of rabeprazole were described with good precision following administration of rabeprazole across a range of doses and in a range of formulations.
KeywordsRabeprazole Population Pharmacokinetic Model Lean Body Weight Pediatric Subject Residual Unexplained Variability
Conflict of interest
The principal investigator was Holly Kimko, Janssen Research & Development. AT, EM, HK, and WT are employees of Janssen Research & Development, LLC and received stock options. SM and BG are employees of Model Answers Pty Ltd, which was paid consulting fees by Janssen Research & Development, LLC for this work. No authors have any financial relationships with organizations that might have an interest in the submitted work.
- 1.Rudolph CD, Mazur LJ, Liptak GS, Baker RD, Boyle JT, Colletti RB, et al. Guidelines for evaluation and treatment of gastroesophageal reflux in infants and children: recommendations of the North American Society for Pediatric Gastroenterology and Nutrition. J Pediatr Gastroenterol Nutr. 2001;32(Suppl 2):S1–31.PubMedCrossRefGoogle Scholar
- 11.Zannikos PN, Doose DR, Leitz GJ, Rusch S, Gonzalez MD, Solanki B, et al. Pharmacokinetics and tolerability of rabeprazole in children 1 to 11 years old with gastroesophageal reflux disease. J Pediatr Gastroenterol Nutr. 2011;52(6):691–701. doi: 10.1097/MPG.0b013e318207834d.PubMedCrossRefGoogle Scholar
- 16.Janssen. PARIET® tablets (rabeprazole sodium): product information. Macquarie Park: Janssen; 2013.Google Scholar
- 17.Bonate PL. Pharmacokinetic-pharmacodynamic modeling and simulation. New York: Springer; 2006.Google Scholar
- 21.Kleiber M. Body size and metabolism. Hilgardia. 1932;6:315–53.Google Scholar
- 22.Rubner M. Uber den Einfluss der Korpergrosse auf Stoffund Kraftwechsel. Zeitscrift fur Biologie (Munich). 1883;19:535–62.Google Scholar