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

• Published in: Circulation (New York, N.Y.) Vol. 100; no. 11; pp. 1175 - 1181
• Main Authors: Harder, Sebastian, Kirchmaier, Carl M., Krzywanek, Hans Jürgen, Westrup, Dagmar, Bae, Jin-Woo, Breddin, Hans Klaus
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 14.09.1999; American Heart Association, Inc
• Subjects: Abciximab; Adult; Antibodies, Monoclonal - pharmacokinetics; Antibodies, Monoclonal - pharmacology; Biological and medical sciences; Bleeding Time; Blood. Blood coagulation. Reticuloendothelial system; Humans; Immunoglobulin Fab Fragments - pharmacology; Male; Medical sciences; Pharmacology. Drug treatments; Platelet Adhesiveness - drug effects; Platelet Aggregation - drug effects; Platelet Aggregation Inhibitors - pharmacology; Platelet Glycoprotein GPIIb-IIIa Complex - antagonists & inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex - immunology; Thrombin - biosynthesis; Aggregation; Human; Platelet; Abciximab; Pharmacokinetics; Biological activity; Antiplatelet agent
• ISSN: 0009-7322; 1524-4539; 1524-4539
• DOI: 10.1161/01.CIR.100.11.1175

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.