O27?Prospective evaluation of a population pharmacokinetic model of pantoprazole for obese children

摘要

Background Pharmacokinetic (PK) data for proton pump inhibitors, acid suppressive medications commonly prescribed to children, are lacking for obese children who are at greatest risk for acid related disease. Our aim was to evaluate the performance of the only published population PK model of pantoprazole for obese children, in an independent cohort of obese and non-obese children. Methods A published 2-compartment structural model,sup1/sup modified to exclude transit compartments for delayed absorption, was used to predict the PK of pantoprazole (PAN) oral suspension, immediate release (ksuba/sub=7.3 hrsup-1/sup). Calculated population parameters and covariate relationships (e.g., weight, CYP2C19 genotype) were extracted. Predictions were based on dose, sampling times, and covariates from 57 children (6–17 years; 21% obese, 28% overweight) who received a single dose PAN and had plasma PAN concentrations collected at 10 time-points over 8 hours. Model predictive performance was assessed visually and by relative root mean squared error (RMSE), with mean ratio of predicted-to-observed area under the concentration time curve (AUC) compared via one-way ANOVA across weight groups, defined by body mass index for age (10–84th percentile normal-weight, 85–94th percentile overweight, 95th percentile obese; α=0.05, R). Results The model generally over-predicted observed PAN concentrations (RMSE 194%). Ratios of predicted versus observed AUC were not significantly different among obese, overweight and normal-weight children (1.5 vs. 1.7 vs. 2.2, p=0.06); however, a trend toward better model prediction was observed in the subset of obese children. Conclusion Observed PAN PK deviated from model predictions, which may be due to differences in patient demographics or PAN formulation. A validation study using a delayed release PAN formulation is in progress, with the overarching goal of understanding PAN disposition, and appropriate dose selection, for obese children, who are at potential risk for drug over- or under-dosing using commonly employed dosing strategies in pediatrics (e.g., mg/kg, weight-tiered). References Shakhnovich, et al. A Population-Based Pharmacokinetic Model Approach to Pantoprazole Dosing for Obese Children and Adolescents.