McGrath Cole, Koenig Christina, Roenfanz Hanna F, Shen Yuwei, Nicolau David P, Kuti Joseph L
Center for Anti-Infective Research and Development, Hartford Hospital, 80 Seymour Street, Hartford, CT 06102, USA.
Intensive Care Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
J Antimicrob Chemother. 2025 Aug 1;80(8):2109-2116. doi: 10.1093/jac/dkaf177.
The extracorporeal removal of antibiotics in patients requiring continuous renal replacement therapy (CRRT) can be impacted by both individual drug properties as well as factors related to the dialysis prescription. Herein, we describe the detailed methodology for setting up an ex vivo CRRT model to determine the adsorption and transmembrane clearance (CLTM) of cefepime, meropenem, levofloxacin and micafungin across various haemofilters, modes and effluent flow rates.
Two methods to determine CLTM were evaluated to derive optimal dosing regimens and method development: CLSC/SA was calculated by the sieving coefficient (SC) for continuous veno-venous haemofiltration and saturation coefficient (SA) for continuous veno-venous haemodialysis. An alternative calculation CLNCM, was derived from non-compartmental analysis of concentrations from the central reservoir.
The average SC/SA of cefepime, meropenem, levofloxacin and micafungin were 1.01, 1.04, 0.87 and <0.01, respectively, which was concordant with their protein-binding profiles. Effluent rate was the primary driver of CLTM for all drugs except micafungin and could be used to guide proposed dosing regimens. CLSC/SA and CLNCM resulted in similar values for cefepime, meropenem and levofloxacin across the effluent rate range but were discordant for micafungin due to filter adsorption; thereby suggesting both methods could be utilized to evaluate CLTM provided negligible filter adsorption is observed.
These ex vivo methods can be combined with patient pharmacokinetic data to determine optimal drug dosing regimens for CRRT during new drug development.
在需要持续肾脏替代治疗（CRRT）的患者中，抗生素的体外清除可能受到个体药物特性以及与透析处方相关因素的影响。在此，我们描述了建立体外CRRT模型的详细方法，以确定头孢吡肟、美罗培南、左氧氟沙星和米卡芬净在各种血液滤过器、模式和流出液流速下的吸附和跨膜清除率（CLTM）。
评估了两种确定CLTM的方法，以推导最佳给药方案并进行方法开发：通过连续静脉-静脉血液滤过的筛系数（SC）和连续静脉-静脉血液透析的饱和系数（SA）计算CLSC/SA。另一种计算方法CLNCM，是通过对中央储液器中的浓度进行非房室分析得出的。
头孢吡肟、美罗培南、左氧氟沙星和米卡芬净的平均SC/SA分别为1.01、1.04、0.87和<0.01，这与其蛋白质结合情况一致。除米卡芬净外，流出液流速是所有药物CLTM的主要驱动因素，可用于指导建议的给药方案。在整个流出液流速范围内，头孢吡肟、美罗培南和左氧氟沙星的CLSC/SA和CLNCM值相似，但由于滤器吸附，米卡芬净的结果不一致；因此表明，如果观察到滤器吸附可忽略不计，则两种方法均可用于评估CLTM。
这些体外方法可与患者药代动力学数据相结合，以确定新药开发过程中CRRT的最佳给药方案。
