基于人群的奥美拉唑在肥胖儿童和青少年中的药代动力学模型剂量调整方法。
A Population-Based Pharmacokinetic Model Approach to Pantoprazole Dosing for Obese Children and Adolescents.
机构信息
The Children's Mercy Hospital, Kansas City, MO, USA.
University of Missouri-Kansas City School of Medicine, Kansas City, USA.
出版信息
Paediatr Drugs. 2018 Oct;20(5):483-495. doi: 10.1007/s40272-018-0305-1.
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 (AUC)] 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 AUC remained using this dosing approach.
背景和目的
质子泵抑制剂（PPIs）是一种常用于儿童的抑酸药物，其药代动力学数据在肥胖儿童中较为缺乏，而肥胖儿童是胃酸相关疾病的高危人群。在最近的一项多中心研究中，我们发现肥胖儿童的质子泵抑制剂泮托拉唑的总体重校正表观清除率（CL/F）较非肥胖儿童降低。随后，我们建立了一种基于人群的药代动力学（PopPK）模型来描述泮托拉唑的分布，并通过模拟评估了适合肥胖儿科患者的泮托拉唑给药方案。
方法
在唯一一项针对肥胖儿童的 PPI 前瞻性研究中（年龄 6-17 岁；n=40），我们获得了 273 次泮托拉唑和 256 次泮托拉唑砜血浆浓度，单次口服给药后，使用 NONMEM 进行了泮托拉唑模型开发和协变量分析。通过 bootstrap 和预测检查进行模型评估，并将最终模型应用于模拟常见给药方案的系统泮托拉唑暴露。
结果
包含 CYP2C19 基因型和总体重的两室 PopPK 模型提供了最佳拟合。由此产生的典型体重归一化泮托拉唑参数估计值与先前报道的儿童或成人不同，肥胖儿童的泮托拉唑 CL/F 显著降低。在所评估的给药方案中，美国食品和药物管理局批准的体重分层方法可实现泮托拉唑暴露[曲线下面积（AUC）]在先前报道的治疗范围内，而不会对肥胖儿童出现过度或过低预测。
结论
我们的数据表明，肥胖儿童不应经验性地增加 PPI 剂量，并且支持目前 FDA 批准的儿童体重分层剂量方案用于泮托拉唑；然而，使用这种给药方法，泮托拉唑 AUC 的个体间差异仍为 3-5 倍。
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