Population pharmacokinetics of polymyxin B and dosage strategy in critically ill patients with/without continuous renal replacement therapy

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-1). 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.