A Multi-Center Study of Population Pharmacokinetics of Polymyxin B in Critically Ill Patients

Purpose: To develop a population pharmacokinetics (PPK) model for polymyxin B (PB) in critically ill patients, and propose individualized dosing regimens. Methods: Blood samples were collected from intensive care unit (ICU) patients after the third or subsequent PB doses. The NONMEM software was used to construct a PPK model, with a focus on identifying key covariates influencing drug behavior. Patient-specific dosing strategies and probability of target attainment (PTA) were evaluated using Monte Carlo simulations. Results: A total of 56 ICU patients with 350 blood samples were included. A two-compartment model best described the data, with estimated glomerular filtration rate (eGFR) identified as a significant covariate on clearance (CL). The value of CL was 1.68 L/h. The estimated central compartment volume (V 1 ) was 14.3 L, the peripheral compartment volume (V 2 ) was 48.84 L, and the inter-compartmental clearance (Q) was 4.67 L/h. The simulation results demonstrated a positive correlation between probability of target attainment (PTA) and maintenance dose (MD) at a fixed first dose (FD) for any given minimum inhibitory concentration (MIC). Conversely, a similar increase in PTA with higher FD was observed when MD was held constant. Furthermore, achieving therapeutic targets required larger dosing regimens in patients with better renal function. Conclusion: PB clearance is influenced by eGFR in critically ill patients. Higher MIC values or preserved renal function necessitate increased dosing. This study provides tailored dosing recommendations for ICU patients based on renal function and MIC. Keywords: polymyxin B, population pharmacokinetics, renal function, ICU, dosage regimen