Adamiszak Arkadiusz, Pietrzkiewicz Krzysztof, Bartkowska-Śniatkowska Alicja, Smuszkiewicz Piotr, Kusza Krzysztof, Grześkowiak Edmund, Bienert Agnieszka
Department of Pharmacology, Poznan University of Medical Sciences, 60-806 Poznan, Poland.
Doctoral School, Poznan University of Medical Sciences, 60-812 Poznan, Poland.
Antibiotics (Basel). 2025 Mar 27;14(4):347. doi: 10.3390/antibiotics14040347.
: We aimed to develop a population pharmacokinetic (PopPK) model and evaluate dosing regimens for different renal clearances and continuous renal replacement therapy (CRRT) settings. : Data were collected from four studies in intensive care unit (ICU) adult patients receiving 400-600 mg of ceftaroline every 8-12 h in a one-hour infusion. The PopPK model was developed according to non-linear mixed effects modeling implemented in Monolix 2024R1. To investigate dosing recommendations, Monte Carlo simulations and probability of target attainment (PTA) analysis were performed in Simulx 2024R1. : We collected 296 plasma concentrations from 29 non-CRRT patients and 24 pre-filter (systemic), 23 post-filter, and 23 effluent concentrations from four CRRT patients using WebPlotDigitizer (Version 4.7). A five-compartment model, with the first-order elimination from the central compartment and additional elimination with the effluent during CRRT, best described the ceftaroline concentrations. Creatinine clearance () was identified as a covariate on the clearance of elimination () and CRRT modality on the central and peripheral compartments' volumes and intercompartmental clearance. The results of dosage simulations for different CRRT modalities and , (MIC = 0.25 mg/L) and methicillin-resistant (MRSA) (MIC = 1 mg/L) infections, and assumed 100%ƒT target, revealed that registered ceftaroline dosages are sufficient to achieve assumed PTA, except MRSA infection in patients with augmented renal clearance (ARC). : Our successfully developed model allows flexible PK simulations of ceftaroline, including real-time changes in settings and even temporary or permanent cessation of CRRT. However, the results of our study warrant clinical validation and should be used with caution primarily due to the limited CRRT patient number included in the analysis.
我们旨在建立一个群体药代动力学（PopPK）模型，并评估不同肾脏清除率和持续肾脏替代治疗（CRRT）设置下的给药方案。数据来自四项针对重症监护病房（ICU）成年患者的研究，这些患者每8 - 12小时接受400 - 600毫克头孢洛林，静脉输注1小时。PopPK模型是根据Monolix 2024R1中实施的非线性混合效应建模开发的。为了研究给药建议，在Simulx 2024R1中进行了蒙特卡洛模拟和目标达成概率（PTA）分析。我们使用WebPlotDigitizer（版本4.7）从29例非CRRT患者中收集了296份血浆浓度，以及从4例CRRT患者中收集了24份滤前（全身）、23份滤后和23份流出液浓度。一个五室模型，其中中央室以一级速率消除，CRRT期间流出液额外消除，能最好地描述头孢洛林浓度。肌酐清除率（）被确定为消除清除率（）的协变量，CRRT模式则影响中央室和外周室的容积以及室间清除率。针对不同CRRT模式、以及 （MIC = 0.25毫克/升）和耐甲氧西林金黄色葡萄球菌（MRSA）（MIC = 1毫克/升）感染的剂量模拟结果，并假设100%ƒT目标，显示除了肾脏清除率增加（ARC）患者的MRSA感染外，已注册的头孢洛林剂量足以达到假设的PTA。我们成功开发的模型允许对头孢洛林进行灵活的药代动力学模拟，包括CRRT设置的实时变化，甚至CRRT的暂时或永久停止。然而，我们研究的结果需要临床验证，并且主要由于分析中纳入的CRRT患者数量有限，应谨慎使用。
