Burns, Trauma and Critical Care Research Centre, The University of Queensland, Brisbane, Queensland, Australia.
Antimicrob Agents Chemother. 2010 Sep;54(9):3635-40. doi: 10.1128/AAC.00222-10. Epub 2010 Jun 14.
The objective of the present prospective pharmacokinetic study was to describe the variability of plasma gentamicin concentrations in critically ill patients with acute kidney injury (AKI) necessitating extended daily diafiltration (EDD-f) using a population pharmacokinetic model and to subsequently perform Monte Carlo dosing simulations to determine which dose regimen achieves the pharmacodynamic targets the most consistently. We collected data from 28 gentamicin doses in 14 critically ill adult patients with AKI requiring EDD-f and therapeutic gentamicin. Serial plasma samples were collected. A population pharmacokinetic model was used to describe the pharmacokinetics of gentamicin and perform Monte Carlo simulations with doses of between 3 mg/kg of body weight and 7 mg/kg and at various time points before commencement of EDD-f to evaluate the optimal dosing regimen for achieving pharmacodynamic targets. A two-compartment pharmacokinetic model adequately described the gentamicin clearance while patients were on and off EDD-f. The plasma half-life of gentamicin during EDD-f was 13.8 h, whereas it was 153.4 h without EDD-f. Monte Carlo simulations suggest that dosing with 6 mg/kg every 48 h either 30 min or 1 h before the commencement of EDD-f results in 100% attainment of the target maximum concentration drug in plasma (<10 mg/liter) and sufficient attainment of the target area under the concentration-time curve from 0 to 24 h (AUC(0-24); 70 to 120 mg.h/liter). None of the simulated dosing regimens satisfactorily achieved the targets of the minimum concentrations of drug in plasma (<1.0 mg/liter) at 24 h. In conclusion, dosing of gentamicin 30 min to 1 h before the commencement of an EDD-f treatment enables attainment of target peak concentrations for maximal therapeutic effect while enhancing drug clearance to minimize toxicity. Redosing in many patients should occur after 48 h, and we recommend the use of therapeutic drug monitoring to guide dosing to optimize achievement of the AUC(0-24) targets.
本前瞻性药代动力学研究的目的是描述接受每日延长透析滤过（EDD-f）的急性肾损伤（AKI）危重症患者的血浆庆大霉素浓度的变异性，并使用群体药代动力学模型来进行蒙特卡罗给药模拟，以确定哪种剂量方案最能一致地达到药效学目标。我们收集了 14 名接受 EDD-f 治疗和治疗性庆大霉素治疗的 AKI 危重症成年患者的 28 个庆大霉素剂量数据。采集了一系列血浆样本。使用群体药代动力学模型来描述庆大霉素的药代动力学，并在开始 EDD-f 之前的不同时间点，使用 3 至 7mg/kg 体重的剂量进行蒙特卡罗模拟，以评估实现药效学目标的最佳给药方案。当患者接受和不接受 EDD-f 治疗时，两室药代动力学模型均可充分描述庆大霉素的清除率。EDD-f 期间庆大霉素的血浆半衰期为 13.8 小时，而无 EDD-f 时为 153.4 小时。蒙特卡罗模拟表明，在开始 EDD-f 前 30 分钟或 1 小时给予 6mg/kg 的剂量，每 48 小时给药 1 次，可使 100%达到血浆中目标最大浓度药物（<10mg/l），并且从 0 到 24 小时的浓度-时间曲线下面积（AUC(0-24)）达到 70-120mg.h/liter。没有一种模拟的给药方案能满意地达到 24 小时时血浆中药物最小浓度（<1.0mg/l）的目标。总之，在开始 EDD-f 治疗前 30 分钟至 1 小时给予庆大霉素，可达到最大治疗效果的目标峰值浓度，同时增强药物清除率以最大程度降低毒性。许多患者应在 48 小时后再次给药，我们建议使用治疗药物监测来指导给药，以优化 AUC(0-24)目标的实现。
