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Safety, pharmacokinetics, and pharmacodynamics of 4-hour intravenous infusion of eritoran tetrasodium in healthy Japanese and Caucasian males


Activation of TLR4 signaling by endotoxin is believed to be a primary mediator of sepsis and septic shock, via excessive production of cytokines and proinflammatory mediators [1]. Eritoran tetrasodium (hereafter eritoran), a synthetic analog of the endotoxin constituent lipid A, binds to the TLR4/MD-2 complex and thereby blocks the interaction of endotoxin with TLR4 [2]. Eritoran is being investigated for the treatment of severe sepsis [3]. We report results of a study conducted to assess the single-dose safety and tolerability, as well as pharmacokinetics and pharmacodynamics, of eritoran infusion in Japanese and Caucasian healthy adult males.


This was a double-blind, randomized, single-center, placebo-controlled, ascending single-dose, sequential-group study. Sixty-four subjects (aged 20 to 45 years; BMI 18 to 30 kg/m2) were randomized to four groups: 4 mg total dose (n = 12); 12 mg total dose (n = 24); 28 mg total dose (n = 12); placebo (n = 16). Adverse events were recorded by the investigator. Laboratory assessments included standard hematology and clinical chemistry, lipid analysis, and urinalysis.


There were no serious adverse events. Eritoran in single doses up to 28 mg over 4 hours was well tolerated, with no apparent ethnic differences noted. Plasma concentrations were slightly higher, while clearance and volume of distribution were lower, in Japanese versus Caucasian subjects; these differences were not significant after adjustment for differences in body weight. The ex vivo endotoxin inhibitory activity of eritoran was similar in Japanese and Caucasian subjects. Eritoran was distributed mainly to the HDL fraction in both Japanese and Caucasian subjects.


Eritoran was safe and well tolerated in healthy Japanese and Caucasian subjects. The data do not indicate any need for clinical dose adjustment for possible ethnic-based differences in drug distribution or metabolism.


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Okubo, Y., Aikawa, N., Lynn, M. et al. Safety, pharmacokinetics, and pharmacodynamics of 4-hour intravenous infusion of eritoran tetrasodium in healthy Japanese and Caucasian males. Crit Care 15 (Suppl 1), P265 (2011).

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