Application of Physiologically Based Pharmacokinetic Model to Delineate the Impact of Aging and Renal Impairment on Ceftazidime Clearance

Antibiotics Pub Date : 2024-09-09 DOI:10.3390/antibiotics13090862

Khaled Abduljalil, Iain Gardner, Masoud Jamei

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Abstract

The impact of physiological changes during aging on drug disposition has not always been thoroughly assessed in clinical studies. This has left an open question such as how and to what extent patho- and physiological changes in renal function can affect pharmacokinetics in the geriatric population. The objective of this work was to use a physiologically based pharmacokinetic (PBPK) model to quantify the impact of aging and renal impairment (RI) separately and together on ceftazidime pharmacokinetics (PK). The predicted plasma concentrations and PK parameters from the PBPK model were compared to the observed data in individuals of different ages with or without RI (16 independent studies were investigated in this analysis). Apart from clearance in one study, the predicted ceftazidime PK parameters of young adults, elderly, and in individuals with different levels of renal function were within 2-fold of the observed data, and the observed concentrations fell within the 5th–95th prediction interval from the PBPK model simulations. The PBPK model predicted a 1.2-, 1.5-, and 1.8-fold increase in the plasma exposure (AUC) ratio in individuals aged 40, 60, and 70 years old, respectively, with normal renal function for their age compared to 20-year-old individuals with normal renal function. The impact of RI on ceftazidime was predicted to be less marked in older individuals (a 1.04-, 1.43-, and 2.55-fold change in mild, moderate, or severe RI compared to a healthy age-matched control) than in younger individuals (where a 1.47-, 2.03-, and 3.50-fold increase was predicted in mild, moderate, or severe RI compared to a healthy age-matched control). Utilization of the applied population-based PBPK approach allows delineation of the effects of age from renal disease and can better inform future study design and dosing recommendations in clinical study of elderly patients depending on their age and renal function.

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应用生理学药代动力学模型阐明衰老和肾功能损伤对头孢他啶清除率的影响

在临床研究中，尚未彻底评估衰老过程中生理变化对药物处置的影响。这就留下了一个悬而未决的问题，例如肾功能的病理和生理变化会如何以及在多大程度上影响老年人群的药代动力学。这项工作的目的是使用基于生理学的药代动力学（PBPK）模型来量化衰老和肾功能损害（RI）分别和共同对头孢他啶药代动力学（PK）的影响。将 PBPK 模型预测的血浆浓度和 PK 参数与有或没有 RI 的不同年龄个体的观察数据进行了比较（本分析调查了 16 项独立研究）。除一项研究中的清除率外，预测的头孢他啶在年轻成人、老年人和不同肾功能水平的个体中的 PK 参数均在观察数据的 2 倍以内，观察到的浓度在 PBPK 模型模拟的第 5-95 预测区间内。根据 PBPK 模型预测，与肾功能正常的 20 岁个体相比，肾功能正常的 40 岁、60 岁和 70 岁个体的血浆暴露量（AUC）比值分别增加了 1.2 倍、1.5 倍和 1.8 倍。根据预测，RI 对头孢他啶的影响在老年人中（与健康的年龄匹配对照组相比，轻度、中度或重度 RI 的变化分别为 1.04 倍、1.43 倍和 2.55 倍）不如在年轻人中（与健康的年龄匹配对照组相比，轻度、中度或重度 RI 的变化分别为 1.47 倍、2.03 倍和 3.50 倍）明显。利用基于人群的 PBPK 应用方法，可以从肾脏疾病中划分出年龄的影响，并根据老年患者的年龄和肾功能，为今后的研究设计和临床研究剂量建议提供更好的参考。

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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Antibiotics

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