Harder S, Kirchmaier C M, Krzywanek H J, Westrup D, Bae J W, Breddin H K
Institute of Clinical Pharmacology, University Hospital, Frankfurt am Main, Germany.
Circulation. 1999 Sep 14;100(11):1175-81. doi: 10.1161/01.cir.100.11.1175.
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.
Platelet aggregation (20 micromol/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 microg. kg(-1) x 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 approximately 60 minutes. Bolus followed by infusion of 1.0 and 1.5 microg x kg(-1) x 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 microg x kg(-1) x min(-1) showed effects similar to those observed with the 0.5- and 0. 75-microg x kg(-1) x 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.
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.
本研究描述了人源化抗纤维蛋白原糖蛋白IIb/IIIa受体单克隆抗体的Fab片段YM337在健康男性中的首次给药情况。
在子研究1中，对单次静脉注射0.025、0.05、0.1、0.2和0.4mg/kg YM337后的血小板聚集（20μmol/L ADP）、血小板黏附、纤维蛋白原结合、出血时间以及血浆中YM337浓度进行了研究；在子研究2中，对静脉注射（0.35mg/kg）加6小时不同剂量水平（0.5、0.75、1.0、1.5μg·kg⁻¹·min⁻¹）输注YM337后的上述指标进行了研究，以阿昔单抗作为对照药物（每组5或6名受试者）。静脉注射0.2mg/kg和0.4mg/kg YM337后，纤维蛋白原结合减少>80%，出血时间延长至约60分钟。静脉注射后输注1.0和1.5μg·kg⁻¹·min⁻¹ YM337可使血小板聚集抑制率维持>80%。聚集和出血时间在24小时内恢复正常。静脉注射0.25mg/kg阿昔单抗后输注0.125μg·kg⁻¹·min⁻¹的效果与输注0.5和0.75μg·kg⁻¹·min⁻¹ YM337的效果相似。在53名接受YM337治疗的受试者中，发生了1例短暂性血小板减少症和3起轻微出血事件。给药后2周和2个月未检测到人类抗嵌合抗体。
YM337可有效抑制人体中IIb/IIIa介导的血小板聚集和黏附。这项1期研究的结果将推动对YM337进行进一步的临床评估。
