Yang Mei, Zhao Libo, Wang Xiaohui, Sun Chen, Gao Hengmiao, Wang Xiaoling, Qian Suyun
Department of pharmacy, National Center for Children's Health, Beijing Children's Hospital, Capital Medical University, Beijing, China.
Pediatric intensive care unit, National Center for Children's Health, Beijing Children's Hospital, Capital Medical University, Beijing, China.
Antimicrob Agents Chemother. 2023 May 1;95(5). doi: 10.1128/AAC.02504-20. Epub 2021 Feb 8.
Linezolid is an oxazolidinone antibiotic exhibiting efficacy against multidrug-resistant (MDR) Gram-positive-related infections. However, its population pharmacokinetic (PopPK) profile in Chinese critically ill children has not been characterized. Optimal dosing regimens should be established according to the PopPK/pharmacodynamic(PD) properties of linezolid in the specific population. This work aims to describe the pharmacokinetic (PK) properties of linezolid, assess the factors affecting interpatient variability, and establish an optimized regimen for children in pediatric intensive care unit (PICU). A single-center, prospective, open-labeled PK study was performed. Ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was applied to measure the plasma levels during linezolid treatment. PopPK analysis was conducted using Phoenix NLME software. Sixty-three critically ill pediatric patients were included. The data showed good fit for a two-compartment model with linear elimination. Body weight and aspartate aminotransferase (AST) were the most significant covariates explaining variabilities in linezolid PK for the pediatric population. Therapeutic target was defined as the ratio of the area under drug plasma concentration-time curve over 24 h to minimum inhibitory concentration (AUC/MIC) of >80. Different dosing regimens were evaluated using Monte Carlo simulation to determine the optimal dosage strategy for linezolid. Although the probability of target attainment (PTA) was high (>96%) for 10 mg/kg every 8 h at MIC≤1 mg/L, it was lower than 70% at MIC>1 mg/L. Thus, the dosing regimen required adjustment. When the dosing regimen was adjusted to 15 mg/kg every 6 h, the PTA increased from 63.6% to 94.6% at MIC=2 mg/L, thereby indicating higher treatment success. Children with AST of >40 U/L had significant higher AUC than those with AST of ≤40 U/L (205.45 159.96). Therefore, dosage adjustment was required according to the AST levels. The PopPK characteristics of linezolid in critically ill children were evaluated, and an optimal dosage regimen was constructed based on developmental PopPK/PD model and simulation. (This study has been registered in the Chinese Clinical Trial Registry under no. ChiCTR1900021386.).
利奈唑胺是一种恶唑烷酮类抗生素，对多重耐药（MDR）革兰氏阳性菌相关感染有效。然而，其在中国危重症儿童中的群体药代动力学（PopPK）特征尚未明确。应根据利奈唑胺在特定人群中的PopPK/药效学（PD）特性制定最佳给药方案。本研究旨在描述利奈唑胺的药代动力学（PK）特性，评估影响患者间变异性的因素，并为儿科重症监护病房（PICU）的儿童建立优化给药方案。进行了一项单中心、前瞻性、开放标签的PK研究。采用超高效液相色谱-串联质谱（UPLC-MS/MS）测定利奈唑胺治疗期间的血浆浓度。使用Phoenix NLME软件进行PopPK分析。纳入63例危重症儿科患者。数据显示，线性消除的二室模型拟合良好。体重和天冬氨酸氨基转移酶（AST）是解释儿科人群利奈唑胺PK变异性的最显著协变量。治疗靶点定义为24小时内血浆药物浓度-时间曲线下面积与最低抑菌浓度（AUC/MIC）之比>80。使用蒙特卡罗模拟评估不同给药方案，以确定利奈唑胺的最佳剂量策略。尽管在MIC≤1mg/L时，每8小时10mg/kg的达标概率（PTA）较高（>96%），但在MIC>1mg/L时低于70%。因此，给药方案需要调整。当给药方案调整为每6小时15mg/kg时，在MIC=2mg/L时，PTA从63.6%增加到94.6%，从而表明治疗成功率更高。AST>40U/L的儿童的AUC显著高于AST≤40U/L的儿童（205.45对159.96）。因此，需要根据AST水平调整剂量。评估了利奈唑胺在危重症儿童中的PopPK特征，并基于发育性PopPK/PD模型和模拟构建了最佳给药方案。（本研究已在中国临床试验注册中心注册，注册号为ChiCTR1900021386。）
