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Int J Antimicrob Agents. 2017 Oct;50(4):557-563. doi: 10.1016/j.ijantimicag.2017.06.023. Epub 2017 Jul 12.

Linezolid in liver failure: exploring the value of the maximal liver function capacity (LiMAx) test in a pharmacokinetic pilot study.

Author information

1
Department of Clinical Pharmacy, Institute of Pharmacy, University of Hamburg, Bundesstr. 45, 20146 Hamburg, Germany. Electronic address: sebastian.wicha@uni-hamburg.de.
2
Klinikum Heidenheim, Clinical Pharmacy, Schlosshaustraße 100, 89522 Heidenheim, Germany.
3
Charité-Universitätsmedizin Berlin, Department of Surgery, Campus Charité Mitte, Campus Virchow-Klinikum Augustenburger Platz 1, 13353 Berlin, Germany.

Abstract

Patients in the intensive care unit frequently require antibiotic treatment. Liver impairment poses substantial challenges for dose selection in these patients. The aim of the present pilot study was to assess the novel maximal liver function capacity (LiMAx test) in comparison with conventional liver function markers as covariates of drug clearance in liver failure using linezolid as a model drug. A total of 28 patients with different degrees of liver failure were recruited. LiMAx test as well as plasma, dialysate and urine sampling were performed under linezolid steady-state therapy (600 mg twice daily). NONMEM® was used for a pharmacometric analysis in which the different clearance routes of linezolid were elucidated. Linezolid pharmacokinetics was highly variable in patients with liver failure. The LiMAx score displayed the strongest association with non-renal clearance (CLnon-renal) [ = 4.46∙(body weight/57.9) 0.75∙(LiMAx/221.5)0.388 L/h], which reduced interindividual variability in CLnon-renal from 46.6% to 33.6%, thereby being superior to other common markers of liver function (international normalised ratio, gamma-glutaryl transferase, bilirubin, thrombocytes, alanine aminotransferase, aspartate aminotransferase). For LiMAx < 100 µg/kg/h, 64% of linezolid trough concentrations were above the recommended trough concentration of 8 mg/L, indicating the necessity of therapeutic drug monitoring in these patients. This is the first pilot application of the LiMAx test in a pharmacokinetic (PK) study demonstrating its potential to explain PK variability in linezolid clearance. Further studies with a larger patient collective and further drugs are highly warranted to guide dosing in patients with severe liver impairment.

KEYWORDS:

Dosing; Linezolid; Liver failure; Liver function test

[Indexed for MEDLINE]

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