Pharmacodynamic characterization of the interaction between the glycoprotein IIb/IIIa inhibitor YM337 and unfractionated heparin and aspirin in humans

Abstract

Aims: To investigate the pharmacodynamic interaction of unfractionated heparin (UFH) and acetylic salicylic acid (ASA) on YM337, a monoclonal humanized antibody of the platelet GPIIb/IIIa receptor. Methods: In a randomized, placebo-controlled study three treatment groups each with six healthy volunteers received the following medication: group 1, ASA (3 days) + UFH + YM337 (placebo); group 2, ASA (placebo) + UFH (placebo) + YM337; group 3, ASA + UFH + YM337. Assessments were made over 24 h and included bleeding time (BT), ADP (20 μM)- and collagen (5 μg ml-1)-induced platelet aggregation and PAC1 and CD62 expression measured by flow cytometry. Results: In group 3 BT was prolonged to 35 [median, 16-45 min (1,3 quartile)] after UFH administration, increasing to 45 [median, 42-45 min (1,3 quartile)] after YM infusion (6 h). BT remained elevated to 26 [median, 14-45 min (1,3 quartile)] at 24 h, while groups 1 and 2 returned to normal values. Collagen-induced aggregation was 73% [median, 70-80% (1,3 quartile)] under YM337 alone, 79% [median, 72-80% (1,3 quartile)] under ASA + UFH and reduced only in group 3 to 24% [median, 18-29% (1,3 quartile)]. In both groups receiving active YM337, PAC1 expression showed a reduction to <20% after 6 h of infusion. CD62 expression was not significantly affected by any treatment. Conclusion: UFH and YM337 have strong synergistic effects on BT, while coadministration of ASA strongly augments inhibitory effects of YM337 on collagen-induced platelet aggregation.