A Review of Population Pharmacokinetic Analyses of Linezolid

Abstract

In recent years, many studies on population pharmacokinetics of linezolid have been conducted. This comprehensive review aimed to summarize population pharmacokinetic models of linezolid, by focusing on dosage optimization to maximize the probability of attaining a certain pharmacokinetic-pharmacodynamic parameter in special populations. We searched the PubMed and EMBASE databases for population pharmacokinetic analyses of linezolid using a parametric non-linear mixed-effect approach, including both observational and prospective trials. Of the 32 studies, 26 were performed in adults, four in children, and one in both adults and children. High between-subject variability was determined in the majority of the models, which was in line with the variability of linezolid concentrations previously detected in observational studies. Some studies found that patients with renal impairment, hepatic failure, advanced age, or low body weight had higher exposure and adverse reactions rates. In contrast, lower concentrations and therapeutic failure were associated with obese patients, young patients, and patients who had undergone renal replacement techniques. In critically ill patients, the inter-individual and intra-individual variability was even greater, suggesting that this population is at an even higher risk of underexposure and overexposure. Therapeutic drug monitoring may be warranted in a large proportion of patients given that the Monte Carlo simulations demonstrated that the one-size-fits-all labeled dosing of 600 mg every 12 h could lead to toxicity or therapeutic failure for high values of the minimum inhibitory concentration of the target pathogen. Further research on covariates, including renal function, hepatic function, and drug-drug interactions related to P-glycoprotein could help to explain variability and improve linezolid dosing regimens.

Linezolid Pharmacokinetics and Its Association with Adverse Drug Reactions in Patients with Drug-Resistant Pulmonary Tuberculosis

“…We have demonstrated that a larger trough level was reached when the daily dosage of LZD is 600 mg. There was also a difference in clearance of LZD, from the 8th to 16th week, and this could be due to alterations in renal function with the continued use of LZD, as noticed by other investigators [ 20 , 21 ].…”

Optimization of Therapy and the Risk of Probiotic Use during Antibiotherapy in Septic Critically Ill Patients: A Narrative Review

“…The ratio of the area under the drug plasma concentration–time curve over 24 h to the MIC (AUC/MIC) or percentage time above the MIC (%T > MIC) are predictors of the therapeutic response, and concentrations in the range of 2–8 mcg/mL appear to define the optimal window for acute bacterial infections, while a cut-off value >8 mg/L is an indicator for thrombocytopenia. Thus, TDM based on PK models or continuous infusion over 6 h instead of intermittent infusion is recommended for the optimization of Linezolid treatment to achieve the target AUC/MIC [ 17 , 36 , 37 , 38 , 39 ].…”

Why Product Information Should not be Set in Stone: Lessons from a Decade of Linezolid Therapeutic Drug Monitoring: An Opinion Paper

“…However, Created by the author (DM) with the antibiotic concentration that would inhibit the growth of 90% of tested bacterial isolates (MIC90) and minimal inhibitory concentration (MIC) range adapted from Kucers' The Use of Antibiotics. 14 certain clinical conditions are associated with linezolid underexposure and an increased risk of treatment failure. These include obesity, augmented renal clearance (ARC), critical illness, and/or the presence of concomitant medications, such as rifampicin.…”

“…A recently published review of the population pharmacokinetics of linezolid reported a residual PK variability of nearly 20%. 14…”