Clinical Pharmacokinetics ( IF 4.6 ) Pub Date : 2022-04-04 , DOI: 10.1007/s40262-022-01113-6 Eveline Wallenburg 1 , Rob Ter Heine 1 , Jeroen A Schouten 2, 3 , Jelmer Raaijmakers 4 , Jaap Ten Oever 3, 5 , Eva Kolwijck 6 , David M Burger 1, 3 , Peter Pickkers 2, 3 , Tim Frenzel 2, 3 , Roger J M Brüggemann 1, 3
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Background and Objectives
Although dose optimization studies have been performed for piperacillin and tazobactam separately, a combined integral analysis is not yet reported. As piperacillin and tazobactam pharmacokinetics are likely to show correlation, a combined pharmacokinetic model should be preferred to account for this correlation when predicting the exposure. Therefore, the aim of this study was to describe the pharmacokinetics and evaluate different dosing regimens of piperacillin and tazobactam in critically ill patients using an integral population pharmacokinetic model in plasma and urine.
Methods
In this observational study, a total of 39 adult intensive care unit patients receiving piperacillin–tazobactam as part of routine clinical care were included. Piperacillin and tazobactam concentrations in plasma and urine were measured and analyzed using non-linear mixed-effects modeling. Monte Carlo simulations were performed to predict the concentrations for different dosing strategies and different categories of renal function.
Results
A combined two-compartment linear pharmacokinetic model for both piperacillin and tazobactam was developed, with an output compartment for the renally excreted fraction. The addition of 24-h urine creatinine clearance significantly improved the model fit. A dose of 12/1.5 g/24 h as a continuous infusion is sufficient to reach a tazobactam concentration above the target (2.89 mg/L) and a piperacillin concentration above the target of 100% f T>1×MIC (minimum inhibitory concentration [MIC] ≤ 16 mg/L). To reach a target of 100% f T>5×MIC with an MIC of 16 mg/L, piperacillin doses of up to 20 g/24 h are inadequate. Potential toxic piperacillin levels were reached in 19.6% and 47.8% of the population with a dose of 12 g/24 h and 20 g/24 h, respectively.
Conclusions
A regular dose of 12/1.5 g/24 h is sufficient in > 90% of the critically ill population to treat infections caused by Escherichia coli and Klebsiella pneumoniae with MICs ≤ 8 mg/L. In case of infections caused by Pseudomonas aeruginosa with an MIC of 16 mg/L, there is a fine line between therapeutic and toxic exposure. Dosing guided by renal function and therapeutic drug monitoring could enhance target attainment in such cases.
ClinicalTrials.gov identifier
NCT03738683.
中文翻译：
危重患者血浆和尿液中哌拉西林和他唑巴坦的整体药代动力学分析
背景和目标
尽管已分别对哌拉西林和他唑巴坦进行了剂量优化研究，但尚未报道联合积分分析。由于哌拉西林和他唑巴坦的药代动力学可能表现出相关性，因此在预测暴露量时应首选组合药代动力学模型来解释这种相关性。因此，本研究的目的是使用血浆和尿液中的整体群体药代动力学模型来描述危重患者中哌拉西林和他唑巴坦的药代动力学并评估不同的给药方案。
方法
在这项观察性研究中，共有 39 名成人重症监护病房患者接受哌拉西林-他唑巴坦作为常规临床护理的一部分。使用非线性混合效应模型测量和分析血浆和尿液中哌拉西林和他唑巴坦的浓度。进行蒙特卡罗模拟以预测不同给药策略和不同类别肾功能的浓度。
结果
开发了哌拉西林和他唑巴坦的组合双室线性药代动力学模型，其中输出室用于肾排泄部分。添加 24 小时尿肌酐清除率显着改善了模型拟合。连续输注 12/1.5 g/24 小时的剂量足以使他佐巴坦浓度高于目标值 (2.89 mg/L)，哌拉西林浓度高于目标值 100% f T >1×MIC（最低抑菌浓度） [MIC] ≤ 16 毫克/升）。为了达到 100% f T >5×MIC （MIC 为 16 mg/L）的目标，高达 20 g/24 小时的哌拉西林剂量是不够的。剂量为 12 克/24 小时和 20 克/24 小时的人群分别有 19.6% 和 47.8% 达到潜在有毒哌拉西林水平。
结论
12/1.5 g/24 h 的常规剂量足以治疗 90% 以上的危重人群，治疗MIC ≤ 8 mg/L的大肠杆菌和肺炎克雷伯菌引起的感染。如果铜绿假单胞菌引起的感染（MIC 为 16 mg/L），则治疗和毒性暴露之间存在细微差别。在这种情况下，由肾功能和治疗药物监测指导的剂量可以提高目标的实现。
ClinicalTrials.gov 标识符
NCT03738683。
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