Antimicrobial Pharmacodynamics and Therapeutics, Department of Molecular and Clinical, Pharmacology, University of Liverpool and Royal Liverpool Broadgreen University Hospital Trust, Liverpool, United Kingdom
Pharmacy Department, Hospital del Mar, Parc de Salut Mar, Barcelona, Spain.
Antimicrob Agents Chemother. 2021 May 18;65(6). doi: 10.1128/AAC.02490-20.
The high interindividual variability in the pharmacokinetics (PK) of linezolid has been described, which results in an unacceptably high proportion of patients with either suboptimal or potentially toxic concentrations following the administration of a fixed regimen. The aim of this study was to develop a population pharmacokinetic model of linezolid and use this to build and validate alogorithms for individualized dosing. A retrospective pharmacokinetic analysis was performed using data from 338 hospitalized patients (65.4% male, 65.5 [±14.6] years) who underwent routine therapeutic drug monitoring for linezolid. Linezolid concentrations were analyzed by using high-performance liquid chromatography. Population pharmacokinetic modeling was performed using a nonparametric methodology with Pmetrics, and Monte Carlo simulations were employed to calculate the 100% time >MIC after the administration of a fixed regimen of 600 mg administered every 12 h (q12h) intravenously (i.v.). The dose of linezolid needed to achieve a PTA ≥ 90% for all susceptible isolates classified according to EUCAST was estimated to be as high as 2,400 mg q12h, which is 4 times higher than the maximum licensed linezolid dose. The final PK model was then used to construct software for dosage individualization, and the performance of the software was assessed using 10 new patients not used to construct the original population PK model. A three-compartment model with an absorptive compartment with zero-order i.v. input and first-order clearance from the central compartment best described the data. The dose optimization software tracked patients with a high degree of accuracy. The software may be a clinically useful tool to adjust linezolid dosages in real time to achieve prespecified drug exposure targets. A further prospective study is needed to examine the potential clinical utility of individualized therapy.
利奈唑胺的药代动力学（PK）存在个体间高度变异性，这导致在给予固定方案后，相当比例的患者存在不理想或潜在毒性的浓度。本研究旨在建立利奈唑胺的群体 PK 模型，并利用该模型构建和验证个体化给药的算法。对 338 名接受利奈唑胺常规治疗药物监测的住院患者（65.4%为男性，65.5[±14.6]岁）的回顾性 PK 数据进行了分析。采用高效液相色谱法分析利奈唑胺的浓度。采用 Pmetrics 进行非参数法群体 PK 建模，采用蒙特卡罗模拟计算 600mg 每 12 小时（q12h）静脉内（i.v.）给予固定方案后 100%时间>MIC。根据 EUCAST 分类，所有敏感分离株的 PTA≥90%所需的利奈唑胺剂量估计高达 2400mg q12h，这是最大许可利奈唑胺剂量的 4 倍。然后使用最终 PK 模型构建用于剂量个体化的软件，并使用未用于构建原始群体 PK 模型的 10 名新患者评估软件的性能。具有零级 i.v.输入和中央室从一级清除的吸收室的三房室模型最佳描述了数据。剂量优化软件高度准确地跟踪患者。该软件可能是一种临床上有用的工具，可实时调整利奈唑胺剂量，以达到预设的药物暴露目标。需要进一步的前瞻性研究来检验个体化治疗的潜在临床实用性。
