Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Department of Pharmacy, Singapore General Hospital, Singapore, Singapore; Emerging Infectious Diseases, Duke-NUS Medical School, Singapore, Singapore.
Clin Microbiol Infect. 2023 Sep;29(9):1174-1181. doi: 10.1016/j.cmi.2023.05.018. Epub 2023 May 20.
To develop a population pharmacokinetic (PK) model with data from the largest polymyxin B-treated patient population studied to date to optimize its dosing in hospitalized patients.
Hospitalized patients receiving intravenous polymyxin B for ≥48 hours were enrolled. Blood samples were collected at steady state and drug concentrations were analysed by liquid chromotography tandem mass spectrometry (LC-MS/MS). Population PK analysis and Monte Carlo simulations were performed to determine the probability of target attainment (PTA).
One hundred and forty-two patients received intravenous polymyxin B (1.33-6 mg/kg/day), providing 681 plasma samples. Twenty-four patients were on renal replacement therapy, including 13 on continuous veno-venous hemodiafiltration (CVVHDF). A 2-compartment model adequately described the PK with body weight as a covariate on the volume of distribution that affected C, but it did not impact clearance or exposure. Creatinine clearance was a statistically significant covariate on clearance, although clinically relevant variations of dose-normalized drug exposure were not observed across a wide creatinine clearance range. The model described higher clearance in CVVHDF patients than in non-CVVHDF patients. Maintenance doses of ≥2.5 mg/kg/day or ≥150 mg/day had a PTA ≥90% (for non-pulmonary infections target) at a steady state for minimum inhibitory concentrations ≤2 mg/L. The PTA at a steady state for CVVHDF patients was lower.
Fixed loading and maintenance doses of polymyxin B seemed to be more appropriate than weight-based dosing regimens in patients weighing 45-90 kg. Higher doses may be needed in patients on CVVHDF. Substantial variability in polymyxin B clearance and volume of distribution was found, suggesting that therapeutic drug monitoring may be indicated.
建立一个群体药代动力学（PK）模型，该模型的数据来自迄今为止研究过的最大的多粘菌素 B 治疗患者群体，以优化住院患者的用药剂量。
纳入接受静脉注射多粘菌素 B 治疗时间≥48 小时的住院患者。在稳态时采集血样，并采用液相色谱串联质谱法（LC-MS/MS）分析药物浓度。进行群体 PK 分析和蒙特卡罗模拟，以确定目标达标率（PTA）。
142 名患者接受静脉注射多粘菌素 B（1.33-6mg/kg/天），共提供 681 个血浆样本。24 名患者接受肾脏替代治疗，包括 13 名连续静脉-静脉血液透析滤过（CVVHDF）患者。2 室模型能很好地描述 PK，体重是分布容积的协变量，影响 C，但不影响清除率或暴露量。肌酐清除率是清除率的统计学显著协变量，但在广泛的肌酐清除率范围内，未观察到剂量标准化药物暴露的临床相关变化。该模型描述了 CVVHDF 患者的清除率高于非 CVVHDF 患者。在稳态时，最低抑菌浓度≤2mg/L 时，维持剂量≥2.5mg/kg/天或≥150mg/天，PTA≥90%（针对非肺部感染目标）。CVVHDF 患者的 PTA 较低。
对于体重为 45-90kg 的患者，固定的负荷剂量和维持剂量似乎比基于体重的剂量方案更合适。CVVHDF 患者可能需要更高的剂量。多粘菌素 B 清除率和分布容积的变异性很大，这表明可能需要进行治疗药物监测。
