A population pharmacokinetic model of polymyxin B based on prospective clinical data to inform dosing in hospitalized patients

Objectives: To develop a population pharmacokinetic (PK) model with data from the largest polymyxin B-treated patient population studied to date to optimize its dosing in hospitalized patients.Methods: Hospitalized patients receiving intravenous polymyxin B for & GE;48 hours were enrolled. Blood samples were collected at steady state and drug concentrations were analysed by liquid chromotography tandem mass spectrometry (LC-MS/MS). Population PK analysis and Monte Carlo simulations were performed to determine the probability of target attainment (PTA).Results: One hundred and forty-two patients received intravenous polymyxin B (1.33-6 mg/kg/day), providing 681 plasma samples. Twenty-four patients were on renal replacement therapy, including 13 on continuous veno-venous hemodiafiltration (CVVHDF). A 2-compartment model adequately described the PK with body weight as a covariate on the volume of distribution that affected Cmax, but it did not impact clearance or exposure. Creatinine clearance was a statistically significant covariate on clearance, although clinically relevant variations of dose-normalized drug exposure were not observed across a wide creatinine clearance range. The model described higher clearance in CVVHDF patients than in non-CVVHDF patients. Maintenance doses of & GE;2.5 mg/kg/day or & GE;150 mg/day had a PTA & GE;90% (for non- pulmonary infections target) at a steady state for minimum inhibitory concentrations & LE;2 mg/L. The PTA at a steady state for CVVHDF patients was lower.Discussion: Fixed loading and maintenance doses of polymyxin B seemed to be more appropriate than weight-based dosing regimens in patients weighing 45-90 kg. Higher doses may be needed in patients on CVVHDF. Substantial variability in polymyxin B clearance and volume of distribution was found, suggesting that therapeutic drug monitoring may be indicated. Patrick O. Hanafin, Clin Microbiol Infect 2023;29:1174 & COPY; 2023 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Automated summary

This study developed a population pharmacokinetic model for hospitalized patients receiving polymyxin B, finding factors that may require dose adjustments when using this drug. Substantial variability in drug clearance and distribution was observed, suggesting the need for therapeutic drug monitoring.