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PHARMACOKINETICS AND PHARMACODYNAMICS |
From Eisai Research Institute, Andover, Massachusetts (Dr. Wong, Mr. Rose), and Eisai Medical Research, Clinical Research and Development, Teaneck, New Jersey (Dr. Rossignol, Mr. Kao, Dr. Carter, Dr. Lynn).
E5564, a structural analog of the lipid A portion of lipopolysaccharide
(LPS), is a potent antagonist of the biochemical and physiologic effects of
LPS in several in vitro and in vivo models and is currently under clinical
development as a possible therapeutic for the treatment of sepsis and septic
shock. The objectives of this study were to (1) assess the safety and
tolerability of E5564 following a 30-minute intravenous (IV) infusion, (2)
evaluate the pharmacokinetic profile of E5564, and (3) measure the ability of
E5564 to block LPS stimulation ex vivo in blood taken from subjects up to 8
hours after ending the infusion. Healthy male volunteers (n = 7/dose group)
were randomly assigned to each of four dose levels (350, 1000, 2000, or 3500
µg). Within each dose group, 5 subjects received drug and 2 received
placebo. E5564 or matching placebo was administered by a 30-minute infusion,
and blood samples were collected at predetermined time points. All doses of
E5564 were demonstrated to be safe and well tolerated. E5564 plasma
concentrations were determined using a validated LC/MS/MS method. The
Cmax and AUC of E5564 increased in a dose-proportional manner.
E5564 pharmacokinetics were characterized by a slow clearance (0.67-0.95
mL/h/kg), a small volume of distribution (41-54 mL/kg), and a relatively long
elimination half-life (42-51 h). As measured in the ex vivo assay, E5564
inhibited LPS-induced tumor necrosis factor-
(TNF-) in a
dose-dependent manner, and at the higher doses (2 and 3.5 mg), antagonistic
activity was measurable up to 8 hours postinfusion. E5564 lacked LPS-like
agonist activity at doses up to 3.5 mg. Taken together, we believe that E5564
is a safe, potent antagonist of LPS in blood and will likely benefit patients
in the treatment of LPS-related diseases.
Key Words: Sepsis • E5564 • pharmacokinetics • healthy volunteers • ex vivo • lipopolysaccharide
Address for reprints: Y. Nancy Wong, PhD, Eisai Research Institute, 1 Corporate Drive, Andover, MA 01810.
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