DOSAGE INDIVIDUALIZATION OF LINEZOLID: PRECISION DOSING OF LINEZOLID TO OPTIMISE EFFICACY AND MINIMISE TOXICITY

Antimicrob Agents Chemother. 2021 Apr 5:AAC.02490-20. doi: 10.1128/AAC.02490-20. Online ahead of print.

ABSTRACT

High interindividual variability in the pharmacokinetics (PK) of linezolid has been described, which results in an unacceptably high proportion of patients with either suboptimal or potentially toxic concentrations following the administration of a fixed regimen. The aim of this study was to develop a population pharmacokinetic model of linezolid and use this to build and validate alogorithms for individualised dosing.A retrospective pharmacokinetic analysis was performed using data from 338 hospitalized patients (65.4% male, 65.5(14.6) years) who underwent routine therapeutic drug monitoring TDM for linezolid. Linezolid concentrations were analysed by using high-performance liquid chromatography. Population pharmacokinetic modelling was performed using a nonparametric methodology with Pmetrics and Monte Carlo simulations were employed to calculate the 100% time >MIC after the administration of a fixed regimen of 600 mg q12h i.v. The dose of linezolid needed to achieve a PTA ≥ 90% for all susceptible isolates classified according to EUCAST was estimated to be as high as 2400mg/12h, which is 4 times higher than the maximum licensed linezolid dose.The final pk model was then used to construct software for dosage individualisation and the performance of the software was assessed using 10 new patients not used to construct the original population PK model.A three-compartment model with an absorptive compartment with zero-order i.v. input and first-order clearance from the central compartment best described the data.The dose optimization software tracked patients with a high degree of accuracy. The software may be a clinically useful tool to adjust linezolid dosages in real-time to achieve prespecified drug exposures targets. A further prospective study is needed to examine the potential clinical utility of individualised therapy.

PMID:33820765 | DOI:10.1128/AAC.02490-20