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  • Open Access

Safety, pharmacokinetics, and pharmacodynamics of 4-hour intravenous infusion of eritoran tetrasodium in healthy Japanese and Caucasian males

  • 1,
  • 2,
  • 1,
  • 1,
  • 3,
  • 3,
  • 4,
  • 4,
  • 5,
  • 5 and
  • 1
Critical Care201115 (Suppl 1) :P265

https://doi.org/10.1186/cc9685

  • Published:

Keywords

  • Septic Shock
  • Total Dose
  • Severe Sepsis
  • TLR4 Signaling
  • Drug Distribution

Introduction

Activation of TLR4 signaling by endotoxin is believed to be a primary mediator of sepsis and septic shock, via excessive production of cytokines and proinflammatory mediators [1]. Eritoran tetrasodium (hereafter eritoran), a synthetic analog of the endotoxin constituent lipid A, binds to the TLR4/MD-2 complex and thereby blocks the interaction of endotoxin with TLR4 [2]. Eritoran is being investigated for the treatment of severe sepsis [3]. We report results of a study conducted to assess the single-dose safety and tolerability, as well as pharmacokinetics and pharmacodynamics, of eritoran infusion in Japanese and Caucasian healthy adult males.

Methods

This was a double-blind, randomized, single-center, placebo-controlled, ascending single-dose, sequential-group study. Sixty-four subjects (aged 20 to 45 years; BMI 18 to 30 kg/m2) were randomized to four groups: 4 mg total dose (n = 12); 12 mg total dose (n = 24); 28 mg total dose (n = 12); placebo (n = 16). Adverse events were recorded by the investigator. Laboratory assessments included standard hematology and clinical chemistry, lipid analysis, and urinalysis.

Results

There were no serious adverse events. Eritoran in single doses up to 28 mg over 4 hours was well tolerated, with no apparent ethnic differences noted. Plasma concentrations were slightly higher, while clearance and volume of distribution were lower, in Japanese versus Caucasian subjects; these differences were not significant after adjustment for differences in body weight. The ex vivo endotoxin inhibitory activity of eritoran was similar in Japanese and Caucasian subjects. Eritoran was distributed mainly to the HDL fraction in both Japanese and Caucasian subjects.

Conclusions

Eritoran was safe and well tolerated in healthy Japanese and Caucasian subjects. The data do not indicate any need for clinical dose adjustment for possible ethnic-based differences in drug distribution or metabolism.

Authors’ Affiliations

(1)
Eisai, Inc., Woodcliff Lake, NJ, USA
(2)
Emergency and Critical Care Medicine, School of Medicine, Keio University, Tokyo, Japan
(3)
Eisai, Inc, Andover, MA, USA
(4)
Eisai Co., Ltd, Tokyo, Japan
(5)
The University of British Columbia, Vancouver, Canada

References

  1. Opal SM: Int J Med Microbiol. 2007, 297: 365-377. 10.1016/j.ijmm.2007.03.006View ArticlePubMedGoogle Scholar
  2. Kim HM, et al.: Cell. 2007, 130: 906-917. 10.1016/j.cell.2007.08.002View ArticlePubMedGoogle Scholar
  3. ACCESS: A Controlled Comparison of Eritoran Tetrasodium and Placebo in Patients with Severe Sepsis.[http://clinicaltrials.gov/ct2/show/NCT00334828?term=eritoran&rank=2]]

Copyright

© Okubo et al. 2011

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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