Rossignol Daniel P, Wong Nancy, Noveck Robert, Lynn Melvyn
Eisai Medical Research Inc., Ridgefield Park, New Jersey 07660, USA.
Innate Immun. 2008 Dec;14(6):383-94. doi: 10.1177/1753425908099173.
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.
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.
Every 12-h dosing of E5564 can replace continuous infusion, while maintaining uninterrupted blocking of high-dose LPS.
埃瑞托拉钠（E5564）是内毒素（脂多糖或LPS）脂质A部分的结构类似物，是LPS及其他Toll样受体4（TLR4）配体的拮抗剂。埃瑞托拉钠在动物和人类内毒素血症模型中可在体内定量阻断LPS反应，且具有较长的药代动力学半衰期，但药效学半衰期较短。本研究的目的是评估在健康志愿者中，以三种目标稳态血浆水平（约1、3和10微克/毫升）每日两次输注E5564的安全性、药代动力学和药效学特征。
女性在3天内给予高达77毫克的负荷剂量和维持剂量，男性在6天内给予105毫克的负荷剂量和维持剂量，除药物输注部位出现自限性静脉炎外，均安全且耐受性良好。血浆水平在24小时内达到稳态。C(max)、C(min)和C(88)、AUC(0 -无穷大)呈剂量正比且与性别无关。通过体外LPS激发试验测定的药效学活性表明，E5564和LPS均呈剂量依赖性，血浆中约3微克/毫升或更高水平的E5564可阻断高达1纳克/毫升的LPS。
每12小时给予一次E5564可替代持续输注，同时维持对高剂量LPS的持续阻断。
