Abstract
Pantoprazole is a proton pump inhibitor indicated for the treatment of gastroesophageal reflux disease, a condition that disproportionately affects children with obesity. Appropriately dosing pantoprazole in children with obesity requires understanding the body size metric that best guides dosing, but pharmacokinetic (PK) trials using traditional techniques are limited by the need for larger sample sizes and frequent blood sampling. Physiologically-based PK (PBPK) models are an attractive alternative that can account for physiologic-, genetic-, and drug-specific changes without the need for extensive clinical trial data. In this study, we explored the effect of obesity on pantoprazole PK and evaluated label-suggested dosing in this population. An adult PBPK model for pantoprazole was developed using data from the literature and accounting for genetic variation in CYP2C19. The adult PBPK model was scaled to children without obesity using age-associated changes in anatomical and physiological parameters. Lastly, the pediatric PBPK model was expanded to children with obesity. Three pantoprazole dosing strategies were evaluated: 1 mg/kg total body weight, 1.2 mg/kg lean body weight, and US Food and Drug Administration-recommended weight-tiered dosing. Simulated concentration–time profiles from our model were compared with data from a prospective cohort study (PAN01; NCT02186652). Weight-tiered dosing resulted in the most (>90%) children with pantoprazole exposures in the reference range, regardless of obesity status or CYP2C19 phenotype, confirming results from previously published population PK models. PBPK models may allow for the efficient study of physiologic and developmental effects of obesity on PK in special populations where clinical trial data may be limited.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1394-1408 |
| Number of pages | 15 |
| Journal | CPT: Pharmacometrics and Systems Pharmacology |
| Volume | 13 |
| Issue number | 8 |
| DOIs | |
| State | Published - Aug 2024 |
Funding
E.J.T. receives support from the Eunice Kennedy Shriver National Institute of Child Health & Human Developmental under award number T32HD104576 and the National Institute of General Medicine Sciences of the National Institutes of Health under Award Number T32GM086330. A.J. was supported by a UNC/Allucent Pharmacokinetics/Pharmacodynamics Fellowship. V.E.F. was supported through a UNC/GSK Pharmacokinetics/Pharmacodynamics Post\u2010Doctoral Fellowship. D.G. receives salary support for research from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD096435, R01HD102949, R01HD113201, and HHSN275201000003I). S.J.B. receives support from the National Institutes of Health, the US Food and Drug Administration, the Childhood Arthritis and Rheumatology Research Alliance, Purdue Pharma, and consulting for UCB. He serves on an NIH Data Safety and Monitoring Board. This research was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) under award 5R01HD096435. The pantoprazole pediatric pharmacokinetic data were collected by the Pediatric Trials Network (PTN) through NICHD contract HHSN275201000003I (PI: D. Benjamin) and contract HHSN275201700002C for The Emmes Company (PI: R. Anand). The content is solely the authors' responsibility and does not necessarily represent the official views of the National Institutes of Health.
ASJC Scopus subject areas
- Modeling and Simulation
- Pharmacology (medical)
