Department of Pharmacy, Fujian Medical University Union Hospital, Fuzhou, China.
College of Pharmacy, Fujian Medical University, Fuzhou, China.
Br J Clin Pharmacol. 2023 Dec;89(12):3561-3572. doi: 10.1111/bcp.15855. Epub 2023 Aug 8.
Polymyxin B (PMB) is widely used to treat infections caused by multidrug-resistant Gram-negative pathogens. Currently, the pharmacokinetic data of PMB in patients with liver dysfunction are limited. This study aimed to develop a population pharmacokinetic (PopPK) model of PMB in patients with liver dysfunction and identify the factors affecting PMB pharmacokinetics.
We conducted a retrospective pharmacokinetic study involving 136 adults with different levels of liver function. Nonlinear mixed effects modelling was used to develop a PopPK model of PMB. Monte Carlo simulation was used to design PMB dosage schedules across various liver and renal functions.
PMB pharmacokinetic analyses included 401 steady-state concentrations in 136 adult patients. A one-compartment pharmacokinetic model with first-order absorption and elimination was used to describe the data. The typical population value of PMB clearance was 2.43 L/h and the volume of distribution was 23.11 L. This study revealed that creatinine clearance (CrCL) and Child-Pugh class were significantly associated with PMB pharmacokinetic parameters; however, clinically relevant variations of dose-normalized drug exposure were not significant. For patients with a minimum inhibitory concentration of ≤0.5 mg/L, the appropriate dose was 40-75 mg/12-h. When the dose exceeded 100 mg/12-h, the risk of nephrotoxicity increased significantly.
This study provided PMB pharmacokinetic information for patients with liver dysfunction. Patients with renal and liver dysfunctions may not require an initial dose adjustment. Rather than PopPK-guided dose adjustment, therapeutic drug monitoring of PMB plays a more direct role in optimizing dosing regimens based on its therapeutic window.
多黏菌素 B（PMB）被广泛用于治疗多重耐药革兰氏阴性病原体引起的感染。目前，肝功能不全患者 PMB 的药代动力学数据有限。本研究旨在建立肝功能不全患者 PMB 的群体药代动力学（PopPK）模型，并确定影响 PMB 药代动力学的因素。
我们进行了一项回顾性药代动力学研究，涉及 136 名不同肝功能水平的成年人。采用非线性混合效应模型建立 PMB 的 PopPK 模型。蒙特卡罗模拟用于设计各种肝肾功能下 PMB 的剂量方案。
PMB 药代动力学分析包括 136 名成年患者的 401 个稳态浓度。采用一室模型加一级吸收和消除来描述数据。PMB 清除率的典型人群值为 2.43 L/h，分布容积为 23.11 L。本研究表明，肌酐清除率（CrCL）和 Child-Pugh 分级与 PMB 药代动力学参数显著相关；然而，剂量归一化药物暴露的临床相关变化并不显著。对于最低抑菌浓度≤0.5mg/L 的患者，合适的剂量为 40-75mg/12h。当剂量超过 100mg/12h 时，肾毒性的风险显著增加。
本研究为肝功能不全患者提供了 PMB 的药代动力学信息。患有肾和肝功能不全的患者可能不需要初始剂量调整。与 PopPK 指导的剂量调整相比，PMB 的治疗药物监测在根据其治疗窗优化给药方案方面发挥更直接的作用。
