Pharmacokinetics and pharmacodynamic effects of a new antibody glycoprotein IIb/IIIa inhibitor (YM337) in healthy subjects

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 mu mol/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 mu g . 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 approximate to 60 minutes. Bolus followed by infusion of 1.0 and 1.5 mu g . 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 mu g. kg(-1). min(-1) showed effects similar to those observed with the 0.5- and 0.75-mu g . 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.