I.K. Minichmayr (1,2), M. Zeitlinger (3), A. Schaeftlein (4), C. Kloft (1)
(1) Dept. of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Germany, (2) and Graduate Research Training program PharMetrX, Germany, (3) Dept. of Clinical Pharmacology, Medical University Vienna, Austria, (4) Dept. of Clinical Pharmacy, Saarland University, Saarbruecken, Germany
Objectives: Linezolid (LZD) is an oxazolidinone antibiotic used for the treatment of gram-positive infections. It is approved in a fixed dosing regimen of 600 mg twice daily, irrespective of individual patient characteristics. The objective of the present work was to explore the ability of standard dosing and alternative intensified dosing regimens to achieve pharmacodynamic (PD) targets in plasma as well as in interstitial space fluid as the target site of infections in four heterogeneous populations.
Methods: Simulations were performed in NONMEM® 7.2 using a population pharmacokinetic (PK) model built upon pooled plasma and microdialysis data (of s.c. adipose and muscle tissue) obtained from healthy volunteers and patients with sepsis, diabetes-related foot infections or cystic fibrosis (ntot=51) [1]. The influence of the covariates creatinine clearance (CLCR) and weight (WT) on plasma and target site exposure of LZD was assessed both for standard dosing and intensified dosing regimens (600 mg thrice daily (TID) vs. loading dose preceding standard dosing). For this purpose, the PK/PD indices AUC/MIC and fT>MIC (time during which free concentrations exceed the MIC) were calculated for Day 1 and Day 4 of therapy and compared to the respective target values (AUC/MIC=100, fT>MIC=100%. [2,3]) for the MIC90 of LZD against S. aureus.
Results: For median values of CLCR and WT of the pooled population, septic patients achieved lowest PK/PD indices
(AUC0-24/MIC 57.6, fT>MIC_adipose 68.7%, fT>MIC_muscle 67.0%). Furthermore, LZD exposure decreased with increasing CLCR and decreasing WT. A loading dose of 1200 mg prior to standard dosing led to slightly higher AUC/MIC values on the first day of therapy, while TID dosing resulted in tendentiously higher fT>MIC (e.g. septic patients (TID vs. loading dose): AUC0-24/MIC 85.5 vs. 90.2 , fT>MIC_pl 98.8% vs. 86.8%). Whereas continued TID dosing seemed advantageous for septic patients (typical CL=11.2 L/h), diabetic patients, the subgroup displaying lowest LZD CL (6.35 L/h), were more prone to LZD overexposure (AUC24 400 mg·h/L [4]).
Conclusions: Linezolid exhibits substantial PK variability between and within different populations, exposing patients to a risk of either therapeutic failure or adverse events. Given the importance of rapidly achieving effective concentrations especially in critically ill patients, intensified dosing regimens, e.g. including front-loading, might be particularly beneficial for septic patients.
References:
[1] Minichmayr IK et al. Poster P1714, 24th ECCMID conference, Barcelona, Spain (2014)
[2] Rayner CR et al. Clin Pharmacokinet 42:1411 (2003)
[3] Sandberg A et al. J Antimicrob Chemother 65:962 (2010)
[4] Pea F et al. Antimicrob Agents Chemother 54:4605 (2010)
Reference: PAGE 24 (2015) Abstr 3482 [www.page-meeting.org/?abstract=3482]
Poster: Drug/Disease modeling - Infection