Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Ghent, Belgium.
J Antimicrob Chemother. 2013 Nov;68(11):2600-8. doi: 10.1093/jac/dkt240. Epub 2013 Jun 25.
The objective of this study was to investigate the population pharmacokinetics and pharmacodynamics of amoxicillin and clavulanic acid in critically ill patients.
In this observational pharmacokinetic study, multiple blood samples were taken over one dosing interval of intravenous amoxicillin/clavulanic acid (1000/200 mg). Blood samples were analysed using a validated ultra HPLC-tandem mass spectrometry technique. Population pharmacokinetic analysis and dosing simulations were performed using non-linear mixed-effects modelling.
One-hundred-and-four blood samples were collected from 13 patients. For both amoxicillin and clavulanic acid, a two-compartment model with between-subject variability for both the clearance and the volume of distribution of the central compartment described the data adequately. For both compounds, 24 h urinary creatinine clearance was supported as a descriptor of drug clearance. The mean clearance of amoxicillin was 10.0 L/h and the mean volume of distribution was 27.4 L. For clavulanic acid, the mean clearance was 6.8 L/h and the mean volume of distribution was 19.2 L. Dosing simulations for amoxicillin supported the use of standard dosing regimens (30 min infusion of 1 g four-times daily or 2 g three-times daily) for most patients when using a target MIC of 8 mg/L and a pharmacodynamic target of 50% fT>MIC, except for those with a creatinine clearance >190 mL/min. Dosing simulations for clavulanic acid showed little accumulation when high doses were administered to patients with high creatinine clearance.
Although vast pharmacokinetic variability exists for both amoxicillin and clavulanic acid in intensive care unit patients, current dosing regiments are appropriate for most patients, except those with very high creatinine clearance.
本研究旨在探讨重症患者中阿莫西林和克拉维酸的群体药代动力学和药效学。
在这项观察性药代动力学研究中，对静脉滴注阿莫西林/克拉维酸（1000/200mg）一个给药间隔时间内的多次血样进行了采集。采用经验证的超高效液相串联质谱技术对血样进行分析。采用非线性混合效应模型进行群体药代动力学分析和给药模拟。
从 13 名患者中采集了 104 份血样。对于阿莫西林和克拉维酸，两室模型能够充分描述数据，其中包括清除率和中央室分布容积的个体间变异性。对于两种化合物，24 小时尿肌酐清除率支持作为药物清除率的描述符。阿莫西林的平均清除率为 10.0L/h，平均分布容积为 27.4L。对于克拉维酸，平均清除率为 6.8L/h，平均分布容积为 19.2L。阿莫西林的给药模拟支持在使用目标 MIC 为 8mg/L 和药效学目标为 50%fT>MIC 的情况下，对于大多数患者使用标准剂量方案（30 分钟输注 1g，每日 4 次或 2g，每日 3 次），但对于肌酐清除率>190mL/min 的患者除外。对于高肌酐清除率的患者给予高剂量时，克拉维酸的给药模拟显示出很少的蓄积。
尽管重症监护病房患者中阿莫西林和克拉维酸的药代动力学存在很大的变异性，但对于大多数患者，包括那些肌酐清除率非常高的患者，目前的剂量方案是合适的。
