• 主题
高级搜索  >
历史搜索 清空历史
首页> 美国卫生研究院文献>AAPS PharmSci >A Workflow Example of PBPK Modeling to Support Pediatric Research and Development: Case Study with Lorazepam
【2h】

A Workflow Example of PBPK Modeling to Support Pediatric Research and Development: Case Study with Lorazepam

机译：支持小儿研究和开发的PBPK模型的工作流程示例：劳拉西m的案例研究

代理获取
本网站仅为用户提供外文OA文献查询和代理获取服务，本网站没有原文。下单后我们将采用程序或人工为您竭诚获取高质量的原文，但由于OA文献来源多样且变更频繁，仍可能出现获取不到、文献不完整或与标题不符等情况，如果获取不到我们将提供退款服务。请知悉。
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

The use of physiologically based pharmacokinetic (PBPK) models in the field of pediatric drug development has garnered much interest of late due to a recent Food and Drug Administration recommendation. The purpose of this study is to illustrate the developmental processes involved in creation of a pediatric PBPK model incorporating existing adult drug data. Lorazepam, a benzodiazepine utilized in both adults and children, was used as an example. A population-PBPK model was developed in PK-Sim v4.2® and scaled to account for age-related changes in size and composition of tissue compartments, protein binding, and growth/maturation of elimination processes. Dose (milligrams per kilogram) requirements for children aged 0–18 years were calculated based on simulations that achieved targeted exposures based on adult references. Predictive accuracy of the PBPK model for producing comparable plasma concentrations among 63 pediatric subjects was assessed using average-fold error (AFE). Estimates of clearance (CL) and volume of distribution (Vss) were compared with observed values for a subset of 15 children using fold error (FE). Pediatric dose requirements in young children (1–3 years) exceeded adult levels on a linear weight-adjusted (milligrams per kilogram) basis. AFE values for model-derived concentration estimates were within 1.5- and 2-fold deviation from observed values for 73% and 92% of patients, respectively. For CL, 60% and 80% of predictions were within 1.5 and 2 FE, respectively. Comparatively, predictions of Vss were more accurate with 80% and 100% of estimates within 1.5 and 2 FE, respectively. Using the presented workflow, the developed pediatric model estimated lorazepam pharmacokinetics in children as a function of age.
机译：由于最近美国食品和药物管理局的建议，在儿科药物开发领域中使用基于生理的药代动力学（PBPK）模型引起了人们的极大兴趣。这项研究的目的是说明创建纳入现有成人药物数据的儿科PBPK模型所涉及的发展过程。劳拉西m是一种在成人和儿童中都使用的苯二氮卓类药物，作为一个例子。在PK-Simv4.2®中开发了种群PBPK模型，并对其进行了缩放，以解决与年龄相关的组织区室大小和组成变化，蛋白质结合以及消除过程的生长/成熟的变化。 0-18岁儿童的剂量（毫克每千克）需求量是根据模拟计算得出的，该模拟基于成人参考数据实现了目标暴露。使用平均倍数误差（AFE）评估了PBPK模型在63名儿科受试者中产生可比血浆浓度的预测准确性。使用倍数误差（FE）将15位儿童的清除率（CL）和分布量（Vss）的估计值与观察值进行比较。在线性体重调整后（毫克每公斤），幼儿（1-3岁）的儿童剂量需求超过成人水平。模型得出的浓度估计值的AFE值分别与73％和92％的患者的观察值相差1.5倍和2倍。对于CL，预测的60％和80％分别在1.5和2 FE之内。相比之下，Vss的预测更为准确，分别在1.5 FE和2 FE之内有80％和100％的估计。使用提出的工作流程，已开发的儿科模型评估了儿童的劳拉西m药代动力学与年龄的关系。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
代理获取

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号