Physiologically-based pharmacokinetic modeling of pantoprazole to evaluate the role of CYP2C19 genetic variation and obesity in the pediatric population

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.