Population pharmacokinetic analysis and dosing regimen optimization of eravacycline in critically ill patients with carbapenem-resistant Acinetobacter baumannii pneumonia.

OBJECTIVES

To develop a population pharmacokinetic (PopPK) model of eravacycline in critically ill patients with carbapenem-resistant Acinetobacter baumannii (CRAB) pneumonia, characterize its pharmacokinetic profile, and optimize dosing regimens to ensure adequate drug exposure in this vulnerable population.

METHODS

The plasma concentration of eravacycline was determined using liquid chromatography-tandem mass spectrometry. PopPK analysis was performed using nonlinear mixed-effects modelling, and the optimal dosing regimen was optimized via Monte Carlo simulation.

RESULTS

A total of 104 plasma samples were collected from 18 patients for eravacycline concentration determination. The final PopPK model was a two-compartment model with body weight as a significant covariate on peripheral volume of distribution (V2). The population typical values for CL, central volume of distribution (V1) and V2 in the final model were 14.4 L/h, 177.6 L and 383.2 L, respectively. Monte Carlo simulations demonstrated that the PK/PD target for eravacycline was achievable with a standard dose (1 mg/kg, Q12 h) at an MIC of 0.125 mg/L in patients weighing 41-80 kg. However, this fixed-dosing strategy was suboptimal at higher MICs.

CONCLUSIONS

This study successfully developed the first PopPK model for eravacycline in critically ill patients with CRAB pneumonia. The findings highlight substantial pharmacokinetic variability and demonstrate that weight-based dosing is crucial to ensure effective exposure, underscoring the necessity of PK/PD-guided personalized therapy.