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



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 (min-max) 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/min, 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 two-compartment Michaellis-Menten clearance model with weight, kidney function, and the number of interacting drugs were identified as covariates that best fit the concentration-time data. Cyclosporine had the greatest effect on lowering the maximum elimination rate (Vmax) of linezolid. Empiric linezolid doses of 300 to 450 mg every 12 hours based on eGFR and the number of interacting medications is 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.


Keywords:

CYP2J2; Dosing; Drug-Drug Interactions; Heart; Kidney.



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