Risk of target non-attainment in obese compared to non-obese patients in calculated linezolid therapy

Abstract

Objectives: The aim was to characterize linezolid population pharmacokinetics in plasma and interstitial space fluid of subcutaneous adipose tissue (target site) of obese compared with non-obese patients and to determine dosing regimens enabling adequate therapy using Monte Carlo simulations. Methods: In this prospective, parallel group, open-label, controlled, single-centre trial, 30 surgery patients (15 obese, 15 non-obese) received 600 mg of intravenous linezolid. A population pharmacokinetic analysis characterizing plasma and microdialysis-derived target site pharmacokinetics was followed by Monte Carlo simulations using twice/thrice daily 600e1200 mg short-term and extended infusions of linezolid. Adequacy of therapy was assessed by the probability of pharmacokinetic/pharmacodynamic target attainment for time and exposure-related indices.Results: In the model, lean body weight and obesity status largely explained between-patient variability in linezolid PK parameters (12.0e44.9%). Both factors caused lower area under the concentrationetime curve in typical obese patients in plasma (e20.4%, 95% CI e22.0% to e15.9%) and at target-site (e37.7%, 95% CI e47.1% to e24.2%) compared with non-obese patients. Probability of target attainment showed improvement with increasing linezolid doses. Depending on lean body weight, adequate therapy was partially attained for 900-and 1200-mg linezolid doses and minimum inhibitory concentrations (MICs) 2 mg/L (probability of target attainment 62.5e100%) but could not be reached for MIC ¼ 4 mg/L (probability of target attainment 82.3%). Additionally, lower linezolid distribution into the target site in obese patients as described above might compromise the plasma-based probability of target attainment analysis. Discussion: This analysis revealed risks of linezolid underdosing in empirical antibiotic therapy of most resistant bacteria for obese and non-obese patients. Doubling the standard dose is associated with adequate probability of target attainment throughout most body masses for MIC 2 mg/L. Further clinical studies with adjusted dosing regimens in for example intensive care patients are needed.

Linezolid Concentrations in Plasma and Subcutaneous Tissue are Reduced in Obese Patients, Resulting in a Higher Risk of Underdosing in Critically Ill Patients: A Controlled Clinical Pharmacokinetic Study

“…Post-hoc, exploratory nonlinear modeling of mixed effects with compartment methods has been performed to investigate additional hypothesis-generating questions, such as those relating to different dosing regimens. [52]. Moreover, different body size descriptors, such as the ideal body weight and lean body weight, could be useful for gaining an in-depth understanding of PK [53] and were considered in the exploratory paper mentioned above, whereas we complied with the foreseen protocol analysis based on weight.…”

Meropenem Plasma and Interstitial Soft Tissue Concentrations in Obese and Nonobese Patients—A Controlled Clinical Trial

“…2012-004383-22) and German Clinical trials Register (DRKS00004776). Previous analyses on linezolid and fosfomycin have been already published [ 25 , 26 , 27 ]. Approval for the trial was obtained from the Leipzig University Ethics Committee (121/13-28012013) and the Federal Institute for Drugs and Medical Devices of Germany (BfArM—No.…”

“…As a perioperative antibiotic prophylaxis, patients were given a standard (weight-independent) dose of 1000-mg meropenem (Meronem ® , AstraZeneca GmbH, Wedel, Germany) in combination with 600-mg linezolid (Zyvoxid ® , Pfizer Deutschland GmbH, Berlin, Germany) as a single 30-min infusion after the induction of anesthesia (60–30 min prior to incision) through an additional vein access. An analysis of the linezolid concentrations in these patients was already published separately [ 25 , 26 ] due to the significantly different properties between the two antibiotics. Anesthesia was performed according to clinical standards and left at the discretion of the anesthetist.…”

Which Analysis Approach Is Adequate to Leverage Clinical Microdialysis Data? A Quantitative Comparison to Investigate Exposure and Response Exemplified by Levofloxacin

“…representing the target site for antibiotics [1]. For several antibiotics, considerable PK differences have been observed between plasma and interstitial fluid [2,3]. Consequently, the recent European Medical Agency guideline for the development of new antibacterial drugs recommended sampling at the target site [4], mentioning the use of microdialysis, a minimally invasive sampling technique that allows continuous measurements of drug concentrations in the ISF over time [5].…”

“…Consequently it remains difficult to justify the selection of the more complex and computationally expensive integral-CA over midpoint-CA or NCA for the analysis of clinical microdialysis data. Despite this knowledge gap, recently integral-CA has been regularly employed in analyses of clinical microdialysis data alongside NCA and midpoint-CA [2,15,16]. Thus, a quantitative comparison of NCA, midpoint-CA and integral-CA based on a compound with well-characterised PK and availability of clinical target-site concentration data is required.…”