Wang Peile, Liu Dongmei, Sun Tongwen, Zhang Xiaojian, Yang Jing
Department of Pharmacy, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou, China.
Department of Pharmacy, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Int J Antimicrob Agents. 2022 Nov-Dec;60(5-6):106693. doi: 10.1016/j.ijantimicag.2022.106693. Epub 2022 Nov 11.
There are limited data on the pharmacokinetics (PK) and pharmacodynamics (PD) of polymyxin B in the elderly population. The objective of this study was to develop a population PK model of polymyxin B in elderly patients, determine factors that affect its PK parameters, and propose alternative dosing regimens. Critically ill elderly patients (age ≥65 years) who received intravenous polymyxin B for multi-drug-resistant Gram-negative bacterial infections were enrolled. A population PK model was developed using Phoenix NLME software. Monte Carlo simulations were performed to optimize regimens attaining the PK/PD target of AUC/MIC >50 and target exposure of 50-100 mg‧h/L. Clinical efficacy and nephrotoxicity of polymyxin B treatment were also assessed. A total of 142 polymyxin B concentrations from 23 patients were available. A two-compartment model with first-order elimination was developed, and albumin was the significant covariate of PK parameters. However, albumin had only a slight effect on polymyxin B exposure. Simulation results indicated that two fixed regimens of 50 mg and 75 mg would be sufficient to reach the PK/PD targets when the minimum inhibitory concentrations was ≤0.5 mg/L. With the exception of 1.25 mg/kg for 58 kg, other weight-based regimens (1.25-1.5 mg/kg for 70 kg and 80 kg; twice daily) may result in at least 40% of predicted AUC >100 mg‧h/L. In conclusion, fixed maintenance dosing of 50 mg and 75 mg for polymyxin B may maximize efficacy while balancing nephrotoxicity concerns for elderly patients.
关于多黏菌素B在老年人群中的药代动力学（PK）和药效动力学（PD）的数据有限。本研究的目的是建立老年患者多黏菌素B的群体PK模型，确定影响其PK参数的因素，并提出替代给药方案。纳入因多重耐药革兰氏阴性菌感染接受静脉注射多黏菌素B的老年重症患者（年龄≥65岁）。使用Phoenix NLME软件建立群体PK模型。进行蒙特卡洛模拟以优化给药方案，使其达到AUC/MIC>50的PK/PD目标以及50 - 100 mg‧h/L的目标暴露量。还评估了多黏菌素B治疗的临床疗效和肾毒性。共有来自23例患者的142个多黏菌素B血药浓度数据。建立了具有一级消除的二室模型，白蛋白是PK参数的显著协变量。然而，白蛋白对多黏菌素B的暴露仅有轻微影响。模拟结果表明，当最低抑菌浓度≤0.5 mg/L时，50 mg和75 mg的两种固定给药方案足以达到PK/PD目标。除了58 kg体重患者使用1.25 mg/kg外，其他基于体重的给药方案（70 kg和80 kg体重患者为1.25 - 1.5 mg/kg；每日两次）可能导致至少40%的预测AUC>100 mg‧h/L。总之，多黏菌素B采用50 mg和75 mg的固定维持剂量给药，可能在平衡老年患者肾毒性担忧的同时使疗效最大化。
