Influence of tedizolid on the cytokine response to the endotoxin challenge in healthy volunteers: a cross-over trial.

Abstract

BACKGROUND:

Preclinical data suggested anti-inflammatory properties of tedizolid.

OBJECTIVES:

To investigate the influence of tedizolid on the cytokine response to the human endotoxin challenge and the effect of endotoxaemia on the pharmacokinetics and protein binding of tedizolid.

METHODS:

In this cross-over trial, 14 male healthy volunteers underwent two treatment periods: (A) 200 mg of tedizolid phosphate once daily for 6 days (3 days orally and 3 days intravenously), followed by an intravenous bolus of 2 ng/kg body weight of LPS on the last treatment day; and (B) intravenous bolus of LPS (2 ng/kg body weight) without concomitant tedizolid treatment. Participants underwent first period A or B, separated by at least 6 weeks. Plasma was sampled to assess cytokines and the pharmacokinetics of tedizolid.

RESULTS:

Following the endotoxin challenge, the peak plasma concentration (median [IQR]; 280 [155-502] versus 287 [132-541]  pg/mL; P = 0.875) and AUC0-24 (979 [676-1319] versus 1000 [647-1632]  pg·h/mL; P = 0.638) of interleukin-6 remained unchanged with and without concomitant tedizolid treatment. The peak concentration and AUC0-24 of TNF-α remained also unchanged with and without tedizolid (47 [31-61] versus 54 [27-69]  pg/mL; P = 0.73 and 197 [163-268] versus 234 [146-280]  pg·h/mL; P = 0.875, respectively). The total maximum concentration (mean ± SD; 2.94 ± 0.69 versus 2.96 ± 0.62 mg/L), total AUC0-24 (22.3 ± 3.8 versus 21.1 ± 3.6 mg·h/L) and protein binding (21.4% ± 1.7% versus 21.6% ± 1.9%) of tedizolid were similar with and without the endotoxin challenge.

CONCLUSIONS:

Tedizolid did not attenuate the LPS-induced cytokine response in healthy volunteers. Furthermore, endotoxaemia did not influence the plasma pharmacokinetics of tedizolid.

• Authors: Anselm Jorda, Beatrix Wulkersdorfer, Christian Schörgenhofer, Peter Matzneller, Valentin Al Jalali, Martin Bauer, Michael Wölf-Duchek, Edith Lackner, Christoph Dorn, Bernd Jilma, Markus Zeitlinger
• Journal: The Journal of antimicrobial chemotherapy (J Antimicrob Chemother) Vol. 77 Issue 5 Pg. 1424-1431 (04 27 2022) ISSN: 1460-2091 [Electronic] England
• PMID: 35165727 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2022. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: [email protected].

Chemical References

• Anti-Bacterial Agents
• Cytokines
• Endotoxins
• Lipopolysaccharides
• Oxazolidinones
• Tetrazoles
• tedizolid

Topics

• Anti-Bacterial Agents
• Body Weight
• Cross-Over Studies
• Cytokines
• Endotoxemia
• Endotoxins
• Female
• Healthy Volunteers
• Humans
• Lipopolysaccharides
• Male
• Oxazolidinones
• Tetrazoles