Linezolid Population Pharmacokinetics to Improve Dosing in Cardiosurgical Patients: Factoring a New Drug-Drug Interaction Pathway

Linezolid-induced myelosuppresion is likely in cardiosurgical patients due to reduced kidney function and potential drug-drug interactions. We show through population modeling and simulation that lower doses than the standard coupled with therapeutic drug monitoring are necessary in this vulnerable population.Background Linezolid-induced myelosuppression limits optimal therapy in cardiosurgical patients with deep-seated infections at current doses. Methods Adult patients who received a cardiac surgery intervention and linezolid for a documented or presumed serious gram-positive infection were evaluated. Therapeutic monitoring data, dosing, concomitant medications, and other pertinent laboratory data were collected retrospectively. A population pharmacokinetic model was constructed to identify covariates and test potential drug-drug interactions that may account for interpatient variability. Simulations from the final model identified doses that achieve a target therapeutic trough concentration of 2-8 mg/L. Results This study included 150 patients (79.3% male) with sepsis and hospital-acquired pneumonia in 71.7% as the primary indication. The population had a median (minimum-maximum) age, body weight, and estimated glomerular filtration rate (eGFR) of 66 (30-85) years, 76 (45-130) kg, and 46.8 (4.9-153.7) mL/minute, respectively. The standard linezolid dosage regimen achieved the therapeutic range in only 54.7% of patients. Lower-than-standard doses were necessary in the majority of patients (77%). A 2-compartment Michaelis-Menten clearance model with weight, kidney function, and the number of interacting drugs identified as covariates that best fit the concentration-time data was used. Cyclosporine had the greatest effect on lowering the maximum elimination rate (V-max) of linezolid. Empiric linezolid doses of 300-450 mg every 12 hours based on eGFR and the number of interacting medications are suggested by this analysis. Conclusions Lower empiric linezolid doses in cardiosurgical patients may avoid toxicities. Confirmatory studies are necessary to verify these potential drug interactions.