A Population-Based Pharmacokinetic Model Approach to Pantoprazole Dosing for Obese Children and Adolescents
10.1007/s40272-018-0305-1; PMCID: PMC6178956
© 2018, Springer Nature Switzerland AG. Background and Aims: Pharmacokinetic data for proton pump inhibitors (PPIs), acid-suppression drugs commonly prescribed to children, are lacking for obese children who are at greatest risk for acid-related disease. In a recent multi-center investigation, we demonstrated decreased, total body weight adjusted, apparent clearance (CL/F) of the PPI pantoprazole for obese children compared with their non-obese peers. Subsequently, we developed a population-based pharmacokinetic (PopPK) model to characterize pantoprazole disposition and evaluated appropriate pantoprazole dosing strategies for obese pediatric patients, using simulation. Methods: Pharmacokinetic data from the only prospective study of PPIs in obese children (aged 6–17 years; n = 40) included 273 pantoprazole and 256 pantoprazole-sulfone plasma concentrations, after single oral-dose administration, and were used for pantoprazole model development and covariate analysis (NONMEM®). Model evaluation was performed via bootstrapping and predictive checks, and the final model was applied to simulate systemic pantoprazole exposures for common dosing scenarios. Results: A two-compartment PopPK model, which included CYP2C19 genotype and total body weight, provided the best fit. Resultant, typical, weight-normalized pantoprazole parameter estimates were different than previously reported for children or adults, with significantly reduced pantoprazole CL/F for obese children. Of the dosing scenarios evaluated, the weight-tiered approach, approved by the US Food and Drug Administration, achieved pantoprazole exposures [area under the curve (AUC0–∞)] within ranges previously reported as therapeutic, without over- or under-prediction for obese children. Conclusions: Our data argue against empiric dose escalation of PPIs for obese children and support current FDA-approved pediatric weight-tiered dosing for pantoprazole; however, 3- to 5-fold inter-individual variability in pantoprazole AUC0–∞ remained using this dosing approach.
Shakhnovich, V., Brian Smith, P., Guptill, J. T., James, L. P., Collier, D. N., Wu, H., Livingston, C. E., Zhao, J., Kearns, G. L., Cohen-Wolkowiez, M. A Population-Based Pharmacokinetic Model Approach to Pantoprazole Dosing for Obese Children and Adolescents Pediatric Drugs 20, 483-495 (2018).