Earp Justin C, Mehrotra Nitin, Peters Kristina E, Fiorentino Robert P, Griebel Donna, Lee Sue C, Mulberg Andrew, Röhss Kerstin, Sandström Marie, Taylor Amy, Tornøe Christoffer W, Wynn Erica L, Van der Walt Jan-Stefan, Garnett Christine
*US Food and Drug Administration, Center for Drug Evaluation and Research, Silver Spring, MD †Former Employee of AstraZeneca R&D Mölndal, Mölndal, Sweden ‡Novo Nordisc, Aalborg Øst, Denmark §Department of Biopharmaceutical Sciences, Uppsala University, Uppsala, Sweden ||Global Clinical Pharmacology and Exploratory Development, Astellas Pharma Europe B.V., Leiden, The Netherlands.
J Pediatr Gastroenterol Nutr. 2017 Sep;65(3):272-277. doi: 10.1097/MPG.0000000000001467.
Food and Drug Administration approval of proton-pump inhibitors for infantile gastroesophageal reflux disease has been limited by intrapatient variability in the clinical assessment of gastroesophageal reflux disease. For children 1 to 17 years old, extrapolating efficacy from adults for IV esomeprazole was accepted. The oral formulation was previously approved in children. Exposure-response and exposure matching analyses were sought to identify approvable pediatric doses.
Intragastric pH biomarker comparisons between children and adults were conducted. Pediatric doses were selected to match exposures in adults and were based on population pharmacokinetic (PK) modeling and simulations with pediatric esomeprazole data. Observed IV or oral esomeprazole PK data were available from 50 and 117 children, between birth and 17 years, respectively, and from 65 adults, between 20 and 48 years. A population PK model developed using these data was used to simulate steady-state esomeprazole exposures for children at different doses to match the observed exposures in adults.
Exposure-response relationships of intragastric pH measures were similar between children and adults. The PK simulations identified a dosing regimen for children that results in comparable steady-state area under the curve to that observed after 20 mg in adults. For IV esomeprazole, increasing the infusion duration to 10 to 30 minutes in children achieves matching Cmax values with adults.
The exposure-matching analysis permitted approval of an esomeprazole regimen not studied directly in clinical trials. Exposure-response for intragastric pH-permitted approval for the treatment of gastroesophageal reflux disease in children in whom it was not possible to evaluate the adult primary endpoint, mucosal healing assessed by endoscopy.
胃食管反流病的临床评估中患者内变异性限制了美国食品药品监督管理局对质子泵抑制剂用于婴儿胃食管反流病的批准。对于1至17岁的儿童，从成人静脉注射埃索美拉唑的疗效进行外推是被认可的。口服制剂此前已在儿童中获批。进行暴露-反应和暴露匹配分析以确定可批准的儿科剂量。
对儿童和成人的胃内pH生物标志物进行比较。选择儿科剂量以匹配成人的暴露量，并基于群体药代动力学（PK）建模以及使用儿科埃索美拉唑数据进行的模拟。分别有50名出生至17岁的儿童以及65名20至48岁的成人可获得静脉注射或口服埃索美拉唑的观察到的PK数据。使用这些数据建立的群体PK模型用于模拟不同剂量儿童的埃索美拉唑稳态暴露量，以匹配在成人中观察到的暴露量。
儿童和成人胃内pH测量的暴露-反应关系相似。PK模拟确定了一种儿童给药方案，其稳态曲线下面积与成人20毫克后观察到的相当。对于静脉注射埃索美拉唑，将儿童的输注持续时间增加至10至30分钟可实现与成人匹配的Cmax值。
暴露匹配分析使得批准了一种未在临床试验中直接研究的埃索美拉唑给药方案。胃内pH的暴露-反应允许批准用于治疗无法评估成人主要终点（通过内镜评估黏膜愈合）的儿童胃食管反流病。
