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

• Published in: Innate immunity (London, England) Vol. 14; no. 6; pp. 383 - 394
• Main Authors: Rossignol, Daniel P., Wong, Nancy, Noveck, Robert, Lynn, Melvyn
• Format: Journal Article
• Language: English
• Published: London, England SAGE Publications 01.12.2008
• Subjects: 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; Toll-like receptor-4; Antagonist; clinical research; sepsis; endotoxin
• ISSN: 1753-4259; 1753-4267
• DOI: 10.1177/1753425908099173

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 µg/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 Cmax, Cmin, and C88, AUC0 —∞ 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 ~3 µg/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.