万古霉素药代动力学研究：基于 PBPK 模型和治疗药物监测。

Pharmacokinetic Study of Vancomycin Using PBPK Modeling and Therapeutic Drug Monitoring.

机构信息

OncoPharma Research Group, Center for Health Technology and Services Research (CINTESIS), Rua Dr. Placido da Costa, 4200-450 Porto, Portugal.

Departament of Pathology, Clinical Chemistry Service, Centro Hospitalar Universitário do Porto (CHUP), Largo Prof. Abel Salazar 4099-001, Porto, Portugal.

出版信息

Curr Drug Metab. 2021;22(2):150-162. doi: 10.2174/1389200221999210101232417.

DOI:10.2174/1389200221999210101232417

PMID:33397252

Abstract

BACKGROUND

Vancomycin has been in clinical use for nearly 50 years and remains the first-line treatment option for Gram-positive infections, including methicillin-resistant Staphylococcus aureus (MRSA). There are multiple strategies to monitor therapy and adjust the dose of this antibiotic. AUC24/MIC ratio has been demonstrated to be the best parameter to predict the effectiveness and safety of vancomycin, and a target ratio of ≥400 is recommended. Still, trough and peak serum levels at steady-state conditions have been used in clinical settings as an accurate and practical method to monitor vancomycin.

METHODS

In this work, we collected and analyzed clinical information of patients being treated in a hospital center in Porto (Portugal) and studied the pharmacokinetics of vancomycin in silico, developing several physiologically based pharmacokinetic (PBPK) models using simulation software GastroPlus™. Different dosages and treatment regimens were studied, and the influence of patients' age, weight and renal function was evaluated; a simulation population was also performed.

RESULTS

A linear effect of dose and a significant influence of weight and renal function in plasmatic levels of vancomycin was observed.

CONCLUSION

The results of this work corroborate the accumulation of vancomycin in plasma and identify some parameters that influence the pharmacokinetics of this antibiotic. The importance of therapeutic monitoring of vancomycin is highlighted, and the usefulness of in silico tools, namely PBPK modeling, is demonstrated.

摘要

背景

万古霉素在临床上已经使用了近 50 年，仍然是治疗革兰氏阳性感染（包括耐甲氧西林金黄色葡萄球菌 [MRSA]）的一线治疗选择。有多种监测治疗并调整这种抗生素剂量的策略。AUC24/MIC 比值已被证明是预测万古霉素疗效和安全性的最佳参数，建议目标比值≥400。尽管如此，在稳态条件下的谷值和峰值血清水平仍在临床环境中用作监测万古霉素的准确和实用方法。

方法

在这项工作中，我们收集和分析了波尔图（葡萄牙）一家医院中心治疗的患者的临床信息，并使用模拟软件 GastroPlus™ 对万古霉素的药代动力学进行了计算机模拟研究，开发了几种基于生理的药代动力学（PBPK）模型。研究了不同的剂量和治疗方案，并评估了患者年龄、体重和肾功能的影响；还进行了模拟人群研究。