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INFLAMMATION AND IMMUNOPHARMACOLOGY

Extended in Vivo Pharmacodynamic Activity of E5564 in Normal Volunteers with Experimental Endotoxemia

Melvyn Lynn, Y. Nancy Wong, Janice L. Wheeler, Richard J. Kao, Carlos A. Perdomo, Robert Noveck, Ramon Vargas, Tony D'Angelo, Sandra Gotzkowsky, F. Gilbert McMahon, Kishor M. Wasan, and Daniel P. Rossignol

Eisai Medical Research Inc., Glenpointe Centre West, Teaneck, New Jersey (M.L., J.L.W., R.J.K., C.A.P., D.P.R.); Eisai Research Institute, Andover, Massachusetts (Y.N.W.); Clinical Research Center, New Orleans, Louisiana (R.N., R.V., T.D., S.G., F.G.M.); and The University of British Columbia, Vancouver, British Columbia, Canada (K.M.W.)

E5564 (-D-glucopyranose) is a synthetic antagonist of bacterial endotoxin that has been shown to completely block human endotoxin response. Low doses of E5564 (0.35-3.5 mg) have a long pharmacokinetic half-life, but a surprisingly short ex vivo and in vivo pharmacodynamic half-life (generally less than several hours). To determine whether extended antagonistic activity can be achieved in vivo, this study assesses the pharmacodynamic activity of 4- and 72-h infusions of E5564 into normal volunteers. Administration of 3.5 mg of E5564/h x 72 h completely blocked effects of endotoxin challenge at the end of dosing (72 h), and at 48 and 72 h postdosing. Similarly, a 4-h infusion of E5564, 3 mg/h completely blocked endotoxin administered 8 h postdosing. A lower dose of E5564, 0.5 mg/h x 4 h, ameliorated but did not block most effects of endotoxin 8 h postdosing (p <0.05). Finally, the effect of varying plasma lipoprotein content on E5564 activity was studied in subjects having high or low cholesterol levels (>180 or <140 mg/dl) after 72-h infusion of 252 mg of E5564. No differences were observed. These results demonstrate that E5564 blocks the effects of endotoxin in a human model of clinical sepsis and indicate its potential in the treatment and/or prevention of clinical sepsis.

Address correspondence to: Dr. Melvyn Lynn, Eisai Medical Research Inc., Glenpointe Centre West, 500 Frank W. Burr Blvd., Teaneck, NJ 07666-6741. E-mail: melvyn_lynn{at}eisai.com

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