Influence of tedizolid on the cytokine response to the endotoxin challenge in healthy volunteers: a cross-over trial
JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY(2022)
摘要
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 AUC(0-24) (979 [676-1319] versus 1000 [647-1632] pg center dot h/mL; P = 0.638) of interleukin-6 remained unchanged with and without concomitant tedizolid treatment. The peak concentration and AUC(0-24) of TNF-alpha 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 center dot h/mL; P = 0.875, respectively). The total maximum concentration (mean +/- SD; 2.94 +/- 0.69 versus 2.96 +/- 0.62 mg/L), total AUC(0-24) (22.3 +/- 3.8 versus 21.1 +/- 3.6 mg center dot 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.
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