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

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 C max , C min , and C 88 , AUC 0 —∞ 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.