Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou, China; Henan Engineering Research Center for Application & Translation of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou, China.
Department of General Intensive Care Unit, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Int J Antimicrob Agents. 2024 Mar;63(3):107099. doi: 10.1016/j.ijantimicag.2024.107099. Epub 2024 Jan 26.
Polymyxin B dosing in patients with sepsis is difficult because pathophysiological changes and supportive therapies alter drug pharmacokinetics (PK). This study aimed to investigate the impact of fluid management and renal function on the PK of polymyxin B and to propose alternative dosing regimens.
Patients (aged ≥ 18 y) with sepsis and receiving intravenous polymyxin B for ≥ 96 h were enrolled. Blood samples were collected at steady state. Plasma concentrations were measured by liquid chromatography-tandem mass spectrometry and subjected to population PK modelling. Monte Carlo simulations were used to optimise dosage regimens.
Eighty-three patients with a median (range) daily fluid intake of 4.2 (1.3-8.4) L and a creatinine clearance (CrCL) of 87.5 (17.3-309.7) mL/min were included. Polymyxin B PK was adequately characterised by a two-compartment model. The PK covariate analysis revealed daily fluid intake statistically significantly affected central volume of distribution and central compartment clearance (CL), and CrCL influenced CL. Simulation indicated that a decreased dosing would be suitable for patients with renal dysfunction (CrCL < 40 mL/min), and therapeutic drug monitoring is recommended to avoid exposure fluctuation when patients have fluid overload.
Fluid management as well as renal function are essential factors affecting polymyxin B PK for patients with sepsis, which can help optimise dosage regimens.
脓毒症患者的多粘菌素 B 剂量给药较为困难，因为病理生理学改变和支持性治疗会改变药物药代动力学（PK）。本研究旨在探讨液体管理和肾功能对多粘菌素 B PK 的影响，并提出替代给药方案。
纳入了接受静脉内多粘菌素 B 治疗≥96 h 的脓毒症成年患者（≥18 岁）。在稳态时采集血样。通过液相色谱-串联质谱法测量血浆浓度，并进行群体 PK 建模。通过蒙特卡罗模拟优化剂量方案。
共纳入 83 例患者，中位（范围）日液体摄入量为 4.2（1.3-8.4）L，肌酐清除率（CrCL）为 87.5（17.3-309.7）mL/min。多粘菌素 B PK 可以通过两室模型充分描述。PK 协变量分析显示，日液体摄入量对中央分布容积和中央室清除率（CL）有统计学显著影响，CrCL 影响 CL。模拟表明，肾功能障碍（CrCL<40 mL/min）患者应减少剂量，当患者存在液体超负荷时，建议进行治疗药物监测以避免暴露波动。
液体管理和肾功能是影响脓毒症患者多粘菌素 B PK 的重要因素，可以帮助优化剂量方案。
