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 microm)- and collagen (5 microg 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.

Figure 1

Bleeding time (median box plots, n = 6 for each bar). Acetylic salicylic acid (ASA) + unfractionated heparin (UFH), YM337, □ ASA + UFH + YM337. *P < 0.02 from corresponding value of treatment with YM337 alone.

Figure 2

Aggregation response (median box plots, n = 6 for each bar) to 20 µm adenosindiphosphate (ADP). acetylic salicylic acid (ASA) + unfractionated heparin (UFH), YM337, □ ASA + UFH + YM337, P < 0.02 from corresponding value of treatment with YM337 alone.

Figure 3

Aggregation response (median box plots, n = 6 for each bar) to 5 µg ml⁻¹ collagen. acetylic salicylic acid (ASA) + unfractionated heparin (UFH), YM337, □ ASA + UFH + YM337. *P < 0.02 from corresponding value of treatment with YM337 alone.