Background
Linezolid belongs to oxazolidinone class of antibiotics and is primarily used for the treatment of sever infections caused by methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin resistant Enterococcus (VRE). It inhibits bacterial protein synthesis by blocking the formation of initiation complex in ribosomes. Linezolid is eliminated through both renal and hepatic routes. It is classified under Reserve group of AWaRe classification by World Health Organization. Being a narrow therapeutic index drug, linezolid needs stringent dosing considerations for safe and effective treatment.
Methods:
A plasma concentration data of 347 samples from 94 patients was used for the development of population pharmacokinetic model on NONMEM software. The influence of significant covariates on clearance (CL) and volume of distribution (Vd) was evaluated by step-wise covariate modeling (SCM) and dosing simulations were performed to maintain the trough concentration withing the target trough concentration range (TTCR) of 2 to 8 mg/L.
Results:
The data was best described by a one-compartment model with first order elimination. The CL was estimated as 3.38 L/h while Vd was 36 L. The between subject variability (BSV) on linezolid clearance was 39.6% and that of Vd was 29.8%. Creatinine clearance (CRCL) and age of the patients were proved significant covariates on CL while no significant covariate was observed for Vd during SCM. The dosing simulations revealed that administration of standard dose of 600 mg is not suitable for all patients and estimated trough concentrations was above 8 mg/L which may result in toxicity.
Conclusion:
The renal status and age of the patients are significant covariates responsible for BSV in linezolid CL and dose of 200 mg, 300 mg, 400 mg and 600 mg are appropriate for patient with CRCL 20 mL/min, 40 mL/min, 80 mL/min and 120 mL/min respectively.