Population Pharmacokinetic Model-Based Optimization of Linezolid Dosing in Hematooncological Patients With Suspected or Proven Gram-Positive Sepsis

Abstract

The objective of this study was to develop a population pharmacokinetic model for linezolid in hematooncological patients with sepsis, and to propose dosing optimization based on pharmacokinetic covariates that would lead to improved achievement of the PK/PD target. Therapeutic drug monitoring data from hematooncological patients treated with linezolid for suspected or proven sepsis were analyzed. A pharmacokinetic population model for linezolid was constructed using a nonlinear mixed-effects modeling approach. Monte Carlo simulations were then used to compare various dosing regimens in terms of PK/PD target attainment. A total of 197 linezolid serum concentrations obtained from 22 patients were included in the analysis. Patients' age was found to be the most predictive covariate for linezolid pharmacokinetics. In a patient with a median age of 59 years, the volume of distribution and clearance of linezolid were 46.2 L and 12.1 L/h, respectively. During the first 4 days of therapy, linezolid clearance decreased by 33%. The probability of PK/PD target attainment increased through the individualization of the dose according to the patient's age, administration of a loading dose, and administration of linezolid via continuous infusion. For this scenario, an easy-to-use nomogram was designed.