Dosage Optimization Using Physiologically Based Pharmacokinetic Modeling for Pediatric Patients with Renal Impairment: A Case Study of Meropenem

IF 3.4 4区医学 Q2 PHARMACOLOGY & PHARMACY

AAPS PharmSciTech Pub Date : 2025-01-16 DOI:10.1208/s12249-024-03026-y

Najia Rahim, Muhammad Sarfraz, Abubakar Bello, Syed Baqir Shyum Naqvi

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Abstract

The pharmacokinetics of renally eliminated antibiotics can be influenced by changes associated with renal function and development in a growing subject. Little is known about the effects of renal insufficiency on the pharmacokinetics of meropenem in pediatric subjects. The aim of this study was to develop a physiologically based pharmacokinetic (PBPK) model of meropenem for pediatric patients that can be used to optimize meropenem dosing in pediatric patients with renal impairment (RI). The PBPK model was developed using GastroPlus™ 9.9 based on clinical data obtained from the literature and then scaled to pediatric patients with RI for dose optimization of meropenem. The goodness of fit of the model was assessed by comparing the predicted values of AUC_0-t, AUC_0-α, and C_max with the observed data and the average fold errors (AFE). The AFE values for AUC_0-t, AUC_0-α, and C_max in the pediatric population were measured to be 1.60, 1.08, and 1.48, respectively. In addition, dose optimization was performed in virtual pediatric populations with varying degrees of RI and a dose reduction to 10 mg/kg and 7.5 mg/kg was recommended for moderate and severe RI, respectively. In all virtual pediatric populations with RI, the plasma concentration reached the recommended time above the minimum inhibitory concentration (MIC) at all optimized doses. The developed PBPK model for meropenem provides a quantitative tool to assess the impact of RI on the pharmacokinetics of meropenem in pediatric patients, which may be useful for optimizing the dosing regimen.

Graphical Abstract

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使用基于生理的药代动力学模型优化儿科肾脏损害患者的剂量：以美罗培南为例

肾脏消除抗生素的药代动力学可能受到与肾脏功能和发展相关的变化的影响。目前对肾功能不全对儿童美罗培南药代动力学的影响知之甚少。本研究的目的是建立一个基于生理的美罗培南儿科患者药代动力学（PBPK）模型，该模型可用于优化美罗培南在儿科肾损害（RI）患者中的剂量。基于文献中获得的临床数据，使用GastroPlus™9.9开发PBPK模型，然后扩展到患有RI的儿科患者中，以优化美罗培南的剂量。将AUC0-t、AUC0-α、Cmax预测值与实测数据及平均折差（AFE）进行比较，评价模型的拟合优度。儿童AUC0-t、AUC0-α和Cmax的AFE值分别为1.60、1.08和1.48。此外，在不同程度的RI的虚拟儿科人群中进行了剂量优化，中度和重度RI的剂量分别减少到10 mg/kg和7.5 mg/kg。在所有具有RI的虚拟儿科人群中，在所有优化剂量下，血浆浓度达到最低抑制浓度（MIC）以上的推荐时间。所建立的美罗培南PBPK模型为评估RI对儿科患者美罗培南药代动力学的影响提供了定量工具，这可能有助于优化给药方案。图形抽象

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

AAPS PharmSciTech 医学-药学

CiteScore

6.80

自引率

3.00%

发文量

264

审稿时长

2.4 months

期刊介绍： AAPS PharmSciTech is a peer-reviewed, online-only journal committed to serving those pharmaceutical scientists and engineers interested in the research, development, and evaluation of pharmaceutical dosage forms and delivery systems, including drugs derived from biotechnology and the manufacturing science pertaining to the commercialization of such dosage forms. Because of its electronic nature, AAPS PharmSciTech aspires to utilize evolving electronic technology to enable faster and diverse mechanisms of information delivery to its readership. Submission of uninvited expert reviews and research articles are welcomed.