Continuous pharmacodynamic activity of eritoran tetrasodium, a TLR4 antagonist, during intermittent intravenous infusion into normal volunteers

Innate Immun. 2008 Dec;14(6):383-94. doi: 10.1177/1753425908099173.

Abstract

Background: Eritoran tetrasodium (E5564), a structural analogue of the lipid A portion of endotoxin (lipopolysaccharide or LPS), is an antagonist of LPS and other Toll-like receptor 4 (TLR4) ligands. Eritoran tetrasodium quantitatively blocks LPS response in vivo in animal and human endotoxemia models and demonstrates a long pharmacokinetic half-life, but a short pharmacodynamic half-life. The objective of this study was to assess the safety, and pharmacokinetic and pharmacodynamic profile of E5564 infused twice-daily at three target steady-state plasma levels of approximately 1, 3 and 10 microg/ml in healthy volunteers.

Results: Loading and maintenance doses of up to 77 mg over 3 days in females and 105 mg over 6 days in males were safe and well-tolerated except for self-limiting phlebitis at the drug infusion site. Plasma levels reached steady state by 24 h. The C(max), C(min), and C(88), AUC(0 -infinity) were dose proportional and gender independent. Pharmacodynamic activity measured by an ex vivo LPS challenge assay, demonstrated dose-dependence for both E5564 and LPS and plasma levels of approximately 3 microg/ml E5564 or greater blocked up to 1 ng/ml LPS.

Conclusions: Every 12-h dosing of E5564 can replace continuous infusion, while maintaining uninterrupted blocking of high-dose LPS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Dose-Response Relationship, Drug
  • Endotoxemia / drug therapy
  • Female
  • Humans
  • Infusions, Intravenous
  • Lipid A / administration & dosage
  • Lipid A / adverse effects
  • Lipid A / analogs & derivatives*
  • Lipid A / pharmacokinetics
  • Lipopolysaccharides / antagonists & inhibitors*
  • Male
  • Metabolic Clearance Rate
  • Phlebitis / etiology
  • Toll-Like Receptor 4 / antagonists & inhibitors*

Substances

  • E5564
  • Lipid A
  • Lipopolysaccharides
  • TLR4 protein, human
  • Toll-Like Receptor 4