Skip to main content

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

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.

References

  1. 1.

    Opal SM: Int J Med Microbiol. 2007, 297: 365-377. 10.1016/j.ijmm.2007.03.006

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Kim HM, et al.: Cell. 2007, 130: 906-917. 10.1016/j.cell.2007.08.002

    CAS  Article  PubMed  Google Scholar 

  3. 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]]

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Y Okubo.

Rights and permissions

This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and Permissions

About this article

Cite this article

Okubo, Y., Aikawa, N., Lynn, M. et al. Safety, pharmacokinetics, and pharmacodynamics of 4-hour intravenous infusion of eritoran tetrasodium in healthy Japanese and Caucasian males. Crit Care 15, P265 (2011). https://doi.org/10.1186/cc9685

Download citation

Keywords

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