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.


RESULTS
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.


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.
Harder
S
S
Institute of Clinical Pharmacology, University Hospital, Frankfurt am Main, Germany. harder@em.uni-frankfurt.de
Kirchmaier
C M
CM
Krzywanek
H J
HJ
Westrup
D
D
Bae
J W
JW
Breddin
H K
HK
D000077284:Abciximab; D000328:Adult; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001760:Bleeding Time; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000494:pharmacology*; D008297:Male; D010973:Platelet Adhesiveness / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors* / Q000276:immunology; D013917:Thrombin / Q000096:biosynthesis
D000911:Antibodies, Monoclonal; D007140:Immunoglobulin Fab Fragments; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D013917:Thrombin; D000077284:Abciximab