Abdul-Aziz Mohd H, Diehl Arne, Liu Xin, Cheng Vesa, Corley Amanda, Gilder Eileen, Levkovich Bianca, McGuinness Shay, Ordonez Jenny, Parke Rachael, Pellegrino Vincent, Wallis Steven C, Fraser John F, Shekar Kiran, Roberts Jason A
University of Queensland Centre for Clinical Research (UQCCR), Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia.
Department of Clinical Pharmacy, Faculty of Pharmacy, Universiti Teknologi MARA, Puncak Alam, Malaysia.
Antimicrob Agents Chemother. 2025 Feb 13;69(2):e0143524. doi: 10.1128/aac.01435-24. Epub 2024 Dec 18.
This study aimed to describe the population pharmacokinetics of caspofungin in critically ill patients receiving extracorporeal membrane oxygenation (ECMO) and to identify dosing regimens with a high likelihood of achieving effective exposures. Serial blood samples were collected over a single-dosing interval during ECMO. Total plasma concentrations were measured by a validated chromatographic assay. A population pharmacokinetic model was built and Monte Carlo dosing simulations were performed using Monolix. The probability of target attainment (PTA) and fractional target attainment (FTA) rates were simulated for various caspofungin dosing regimens against , , and . In all, 64 plasma concentration-time points were obtained from 8 critically ill patients receiving ECMO. Plasma concentration-time data for caspofungin were best described by a one-compartment model with first-order elimination. Lean body weight was identified as a significant covariate of volume of distribution. The typical volume of distribution and clearance of caspofungin in this cohort were 8.13 L and 0.55 L/h, respectively. The licensed caspofungin dosing regimen (a loading dose of 70 mg on day 1 followed by a maintenance dose of either 50 mg/day or 70 mg/day) demonstrated optimal PTA rates (≥90%) against with an MIC of ≤0.064 mg/L, with an MIC of ≤0.125 mg/L, and with an MIC of ≤0.064 mg/L. The FTA analysis suggested that the licensed dosing regimen is only optimal (≥95%) against , regardless of lean body weight. A higher-than-standard empirical dosing regimen (e.g., a loading dose of 100 mg on day 1, followed by a maintenance dose of 100 mg daily) is likely advantageous for critically ill patients receiving ECMO.
本研究旨在描述接受体外膜肺氧合（ECMO）的重症患者中卡泊芬净的群体药代动力学，并确定有高可能性实现有效暴露的给药方案。在ECMO期间的单个给药间隔内采集系列血样。通过经过验证的色谱分析法测量总血浆浓度。建立群体药代动力学模型，并使用Monolix进行蒙特卡洛给药模拟。针对不同的卡泊芬净给药方案，模拟达到目标的概率（PTA）和目标达到分数（FTA）率，以对抗、和。总共从8名接受ECMO的重症患者中获得了64个血浆浓度-时间点。卡泊芬净的血浆浓度-时间数据用具有一级消除的单室模型能得到最佳描述。瘦体重被确定为分布容积的一个显著协变量。该队列中卡泊芬净的典型分布容积和清除率分别为8.13 L和0.55 L/h。卡泊芬净的许可给药方案（第1天负荷剂量70 mg，随后维持剂量为50 mg/天或70 mg/天）显示，对于MIC≤0.064 mg/L的，MIC≤0.125 mg/L的，以及MIC≤0.064 mg/L的，达到最佳PTA率（≥90%）。FTA分析表明，无论瘦体重如何，许可给药方案仅对的达到最佳（≥95%）。高于标准的经验性给药方案（例如，第1天负荷剂量100 mg，随后每日维持剂量100 mg）可能对接受ECMO的重症患者有利。
