Dose Optimization of Vancomycin Using a Mechanism-based Exposure-Response Model in Pediatric Infectious Disease Patients
Dose Optimization of Vancomycin Using a Mechanism-based Exposure-Response Model in Pediatric Infectious Disease Patients
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DOI：
10.1016/j.clinthera.2020.10.016
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发表时间：
2021-02-17
影响因子：
3.2
通讯作者：
Yun, Hwi-yeol
中科院分区：
文献类型：
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作者：
Jung, Woo Jin;Park, Jung-Hyuck;Yun, Hwi-yeol
目的：本研究旨在通过模拟革兰氏阳性细菌（GPB）感染儿科患者给药的细菌计数和生物标志物水平，考虑患者体型和器官成熟度，确定适当的万古霉素剂量。方法：使用自然语言处理进行n元分析来检测适当的药效学（PD）标记物在传染病患者中。此外，还建立了一个基于机制的模型，以描述儿科患者的全身暴露量并同时评价PD标志物。然后进行了模拟研究，通过使用一个机制为基础的模型，以评估万古霉素在儿科patients.Findings的最佳剂量：：C-反应蛋白（CRP）被选为PD标记物，从分析类似的270,000摘要在PubMed。此外，还从电子病历中收集了儿科患者（n = 93）的临床结果，包括万古霉素血浆浓度和CRP水平。将具有异速生长标度和成熟函数的万古霉素药代动力学模型构建为一室模型，其中具有用于细菌的额外室。万古霉素血浆浓度对细菌破坏的影响和细菌对CRP产生率的影响均通过使用最大可达效应模型（Emax模型）表示。不仅使用最终模型进行剂量优化模拟，还根据万古霉素对GPB的MIC探索治疗失败的可能性。临床治愈定义为CRP水平低于正常范围的上限。我们的剂量优化模拟表明，万古霉素剂量为10 mg/kg，每8小时一次，是产后年龄儿科患者的最佳维持剂量
Purpose: This study aimed to determine the appropriate vancomycin dosage, considering patient size and organ maturation, by simulating the bacterial count and biomarker level for drug administration in pediatric patients with grampositive bacterial (GPB) infections.Methods: Natural language processing for n-gram analysis was used to detect appropriate pharmacodynamic (PD) markers in infectious disease patients. In addition, a mechanism-based model was established to describe the systemic exposure and evaluate the PD marker simultaneously in pediatric patients. A simulation study was then conducted by using a mechanism-based model to evaluate the optimal dose of vancomycin in pediatric patients.Findings: : C-reactive protein (CRP) was selected as a PD marker from an analysis of similar to 270,000 abstracts in PubMed. In addition, clinical results, including the vancomycin plasma concentrations and CRP levels of pediatric patients (n = 93), were collected from electronic medical records. The vancomycin pharmacokinetic model with allometric scaling and a maturation function was built as a one- compartment model, with an additional compartment for bacteria. Both the effects of vancomycin plasma concentrations on the destruction of bacteria and those of bacteria on CRP production rates were represented by using a maximum achievable effect model (Emax model). Simulation for dose optimization was conducted not only by using the final model but also by exploring the possibility of therapeutic failure based on the MICs of vancomycin for GPB. Clinical cure was defined as when the CRP level fell below the upper limit of the normal range. Our dose optimization simulations suggested a vancomycin dosage of 10 mg/kg every 8 h as the optimal maintenance dose for pediatric patients with a postconceptual age