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

Background: Linezolid is an anti-Gram-positive antimicrobial agent used at a fixed dose of 600 mg every 12 h.

Objectives: 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.

Patients and methods: 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 24 h (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 > 8.06 mg/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.

Results: 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 (CrCL_CKD-EPI)] was the only covariate that improved the model fit. Dose reduction to 450 mg every 12 h may be optimal for patients with coagulase-negative staphylococcal infections and a CrCL_CKD-EPI < 130 mL/min/1.73 m². Dose escalation to 450 mg every 8 h may be optimal for patients with a CrCL_CKD-EPI ≥ 60 mL/min/1.73 m². Escalation to 600 mg every 8 h should not be recommended due to an unacceptable high risk of thrombocytopenia. Patients with CrCL_CKD-EPI ≥ 130 mL/min/1.73 m² and/or co-medication with P-glycoprotein modulators require therapeutic drug monitoring to optimize linezolid doses.

Conclusions: Dosage adjustments of linezolid in this population should be based on CrCL_CKD-EPI estimates, rather than on body size descriptors.