Population Pharmacokinetics and Dosing Considerations for the Use of Linezolid in Overweight and Obese Adult Patients.

Abstract

Linezolid is an anti-Gram-positive antimicrobial agent used at a fixed dose of 600mg every 12h. The objective of this study was to assess the population pharmacokinetics and pharmacodynamics of linezolid in a retrospective cohort of overweight and obese hospitalized patients. Population pharmacokinetic and Monte Carlo simulations were conducted to assess the probability of target attainment (PTA) of an area under the concentration-time curve from time zero to 24h (AUC24)/minimum inhibitory concentration (MIC) ratio>100, defined as the pharmacodynamic target of efficacy, with incremental candidate dosages. Maximum permissible doses were defined as those causing a ≤25% of probability of a linezolid trough of >8.06mg/L, associated with thrombocytopenia. The cumulative fraction of response was calculated for the permissible linezolid doses by testing the PTA against the MIC distributions of a large collection of Staphylococci and Enterococci. A total of 352 trough (minimum) and 293 peak (maximum) linezolid concentrations from 112 patients were included. The final mixed-saturative model accounted for 88% of drug concentrations variability over time, and estimated creatinine clearance [by means of the Chronic Kidney Diseases Epidemiology formula (CrCLCKD-EPI)] was the only covariate that improved the model fit. Dose reduction to 450mg every 12h may be optimal for patients with coagulase-negative staphylococcal infections and a CrCLCKD-EPI <130mL/min/1.73m2. Dose escalation to 450mg every 8h may be optimal for patients with a CrCLCKD-EPI ≥60mL/min/1.73m2. Escalation to 600mg every 8h should not be recommended due to an unacceptable high risk of thrombocytopenia. Patients with CrCLCKD-EPI ≥130mL/min/1.73m2 and/or co-medication with P-glycoprotein modulators require therapeutic drug monitoring to optimize linezolid doses. Dosage adjustments of linezolid in this population should be based on CrCLCKD-EPI estimates, rather than on body size descriptors.