Prediction of Tissue Exposures of Meropenem, Colistin, and Sulbactam in Pediatrics Using Physiologically Based Pharmacokinetic Modeling,Clinical Pharmacokinetics

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Prediction of Tissue Exposures of Meropenem, Colistin, and Sulbactam in Pediatrics Using Physiologically Based Pharmacokinetic Modeling
Clinical Pharmacokinetics ( IF 4.6 ) Pub Date : 2022-08-10 , DOI: 10.1007/s40262-022-01161-y
Shixing Zhu ₁ , Jiayuan Zhang ₁ , Zhihua Lv _{1,

2} , Peijuan Zhu ₃ , Charles Oo ₄ , Mingming Yu _{1,

2} , Sherwin K B Sy ₅

Affiliation

Background

The combination of polymyxins, meropenem, and sulbactam demonstrated efficacy against multi-drug-resistant bacillus Acinetobacter baumannii. These three antibiotics are commonly used against major blood, skin, lung, and heart muscle infections.

Objective

The objective of this study was to predict drug disposition and extrapolate the efficacy in these tissues using a physiologically based pharmacokinetic modeling approach that linked drug exposures to their target pharmacodynamic indices associated with antimicrobial activities against A. baumannii.

Methods

An adult physiologically based pharmacokinetic model was developed for meropenem, colistin, and sulbactam and scaled to pediatrics accounting for both renal and non-renal clearances. The model reliability was evaluated by comparing simulated plasma and tissue drug exposures to observed data. Target pharmacodynamic indices were used to evaluate whether pediatric and adult dosing regimens provided sufficient coverage.

Results

The modeled plasma drug exposures in adults and pediatric patients were consistent with reported literature data. The mean fold errors for meropenem, colistin, and sulbactam were in the range of 0.710–1.37, 0.981–1.47, and 0.647–1.39, respectively. Simulated exposures in the blood, skin, lung, and heart were consistent with reported penetration rates. In a virtual pediatric population aged from 2 to < 18 years, the interpretive breakpoints were achieved in 85–90% of subjects for their targeted pharmacodynamic indices after administration of pediatric dosing regimens consisting of 30 mg/kg of meropenem, and 40 mg/kg of sulbactam three times daily as a 3-h or continuous infusion and 5 mg/kg/day of colistin base activity.

Conclusions

The physiologically based pharmacokinetic modeling supports pediatric dosing regimens of meropenem/colistin/sulbactam in a co-administration setting against infections in the blood, lung, skin, and heart tissues due to A. baumannii.

中文翻译：

使用基于生理学的药代动力学模型预测儿科中美罗培南、粘菌素和舒巴坦的组织暴露

背景

多粘菌素、美罗培南和舒巴坦的组合对多重耐药的鲍曼不动杆菌具有疗效。这三种抗生素通常用于治疗主要的血液、皮肤、肺和心肌感染。

客观的

本研究的目的是使用基于生理学的药代动力学建模方法预测药物在这些组织中的分布和疗效，该方法将药物暴露与其与鲍曼不动杆菌抗菌活性相关的目标药效学指标联系起来。

方法

为美罗培南、粘菌素和舒巴坦开发了基于成人生理学的药代动力学模型，并将其扩展到儿科，同时考虑了肾脏和非肾脏清除率。通过将模拟的血浆和组织药物暴露与观察到的数据进行比较来评估模型的可靠性。目标药效学指数用于评估儿科和成人给药方案是否提供了足够的覆盖率。

结果

成人和儿童患者的模拟血浆药物暴露与报道的文献数据一致。美罗培南、粘菌素和舒巴坦的平均倍数误差分别在 0.710–1.37、0.981–1.47 和 0.647–1.39 范围内。血液、皮肤、肺和心脏中的模拟暴露与报告的渗透率一致。在 2 至 < 18 岁的虚拟儿科人群中，在给予儿科给药方案（包括 30 mg/kg 美罗培南和 40 mg/kg每天 3 次舒巴坦作为 3 小时或连续输注和 5 mg/kg/天的粘菌素基础活性。