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 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.
Rossignol
Daniel P
DP
Eisai Medical Research Inc., Ridgefield Park, New Jersey 07660, USA. dan_rossignol@eisai.com
Wong
Nancy
N
Noveck
Robert
R
Lynn
Melvyn
M
D004305:Dose-Response Relationship, Drug; D019446:Endotoxemia / Q000188:drug therapy; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008050:Lipid A / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors*; D008297:Male; D008657:Metabolic Clearance Rate; D010689:Phlebitis / Q000209:etiology; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors*
C404742:E5564; D008050:Lipid A; D008070:Lipopolysaccharides; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4