Department of Medication, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China; Nanjing Medical Center for Clinical Pharmacy, Nanjing, China.
School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China.
Eur J Pharm Sci. 2022 Aug 1;175:106214. doi: 10.1016/j.ejps.2022.106214. Epub 2022 May 21.
Polymyxin B is served as a last-line agent for Carbapenem-resistant organisms (CRO) infections. This study aimed to establish a population pharmacokinetic (PK) model in patients with/without continuous renal replacement therapy (CRRT), to investigate the relationship between clinical covariates and polymyxin B PK parameters, and to optimize polymyxin B dosing regimens. Blood samples were obtained for each patient at steady state. The plasma concentrations of polymyxin B were determined using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Population PK models were developed using Pirana program and Monte Carlo simulations were conducted. A total of 63 patients accounting for 189 blood samples were included and divided into modeling (n = 49) and validation (n = 14) groups. A two-compartment model described the data well. CRRT, creatinine clearance (CLCR) and Sequential Organ Failure Assessment (SOFA) score were identified as significant covariates of polymyxin B clearance. Monte Carlo simulations indicated that a maintain dose of 75-100 mg q12h was required to meet the target drug exposure in patients receiving CRRT with SOFA ≤ 11 (minimum inhibitory concentration ≤ 1 mg·L). For patients without CRRT, dosage strategy should be adjusted on the basis of different renal functions and SOFA scores. This is the first population PK study that demonstrated CRRT, CLCR and SOFA score had significant effects on polymyxin B clearance in critically ill patients with/without CRRT. More PK data are urgently needed to clarify polymyxin B PK characteristics in patients with/without CRRT.
多粘菌素 B 被用作治疗碳青霉烯类耐药菌（CRO）感染的最后一线药物。本研究旨在建立有/无连续肾脏替代治疗（CRRT）的患者的群体药代动力学（PK）模型，探讨临床协变量与多粘菌素 B PK 参数的关系，并优化多粘菌素 B 的给药方案。在稳态时，为每位患者采集血样。采用高效液相色谱-串联质谱法（HPLC-MS/MS）测定多粘菌素 B 的血浆浓度。使用 Pirana 程序建立群体 PK 模型，并进行 Monte Carlo 模拟。共纳入 63 例患者，共计 189 个血样，分为建模（n=49）和验证（n=14）两组。两室模型能很好地描述数据。CRRT、肌酐清除率（CLCR）和序贯器官衰竭评估（SOFA）评分被确定为多粘菌素 B 清除率的显著协变量。Monte Carlo 模拟表明，对于接受 SOFA ≤ 11 的 CRRT 患者（最小抑菌浓度≤1mg·L），维持剂量为 75-100mg q12h 可达到目标药物暴露量。对于无 CRRT 的患者，应根据不同的肾功能和 SOFA 评分调整剂量策略。这是第一项表明 CRRT、CLCR 和 SOFA 评分对有/无 CRRT 的危重症患者多粘菌素 B 清除率有显著影响的群体 PK 研究。迫切需要更多的 PK 数据来阐明有/无 CRRT 的患者中多粘菌素 B 的 PK 特征。
