This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Harder, S. Articles by Breddin, H. K. Search for Related Content PubMed PubMed Citation Articles by Harder, S. Articles by Breddin, H. K. Related Collections Cardiovascular Pharmacology Anticoagulant mechanisms

(Circulation. 1999;100:1175-1181.)
© 1999 American Heart Association, Inc.

Clinical Investigation and Reports

Pharmacokinetics and Pharmacodynamic Effects of a New Antibody Glycoprotein IIb/IIIa Inhibitor (YM337) in Healthy Subjects

Sebastian Harder, MD; Carl M. Kirchmaier, MD; Hans Jürgen Krzywanek, MD; Dagmar Westrup, MSc; Jin-Woo Bae, MD; Hans Klaus Breddin, MD

From the Institute of Clinical Pharmacology, University Hospital, Frankfurt am Main (S.H., J.-W.B.); the Deutsche Klinik für Diagnostik, Wiesbaden (C.M.K., D.W.); and the International Institute of Thrombosis and Vascular Diseases, Frankfurt am Main (H.J.K., H.K.B.), Germany.

Correspondence to Dr med Sebastian Harder, Institute of Clinical Pharmacology, University Hospital, Theodor Stern Kai 7, D-60590 Frankfurt am Main, Germany. E-mail harder{at}em.uni-frankfurt.de

Background—This study describes the first administration of YM337, the Fab fragment of a humanized monoclonal antibody against the fibrinogen GP IIb/IIIa receptor, in healthy male humans.

Methods and Results—Platelet aggregation (20 µmol/L ADP), platelet adhesion, fibrinogen binding, bleeding time, and YM337 concentrations in plasma were studied in substudy 1 after single boluses of 0.025, 0.05, 0.1, 0.2, and 0.4 mg/kg YM337 and in substudy 2 after a bolus (0.35 mg/kg) plus 6 hours of infusion at different dose levels of YM337 (0.5, 0.75, 1.0, 1.5 µg · kg^-1 · min^-1), with abciximab as reference drug (n=5 or 6 subjects per group). After the 0.2-mg/kg and 0.4-mg/kg boluses, fibrinogen binding was reduced by >80% and bleeding time was prolonged to 60 minutes. Bolus followed by infusion of 1.0 and 1.5 µg · kg^-1 · min^-1 YM337 maintained inhibition of platelet aggregation >80%. Aggregation and bleeding time returned to normal within 24 hours. A bolus of 0.25 mg/kg of abciximab followed by an infusion of 0.125 µg · kg^-1 · min^-1 showed effects similar to those observed with the 0.5- and 0.75-µg · kg^-1 · min^-1 infusion of YM337. In 53 subjects exposed to YM337, 1 case of transient thrombocytopenia and 3 minor bleeding events occurred. No human anti-chimeric antibodies were detected 2 weeks and 2 months after administration.

Conclusions—YM337 effectively inhibits IIb/IIIa-mediated platelet aggregation and adhesion in humans. The results of this phase 1 study will give rise to further clinical evaluation of YM337.

Key Words: platelets • antibodies • glycoproteins • YM337 • abciximab