Glycoprotein IIb/IIIa receptor number and occupancy during chronic administration of an oral antagonist

Long-term treatment with oral glycoprotein (GP) IIb/IIIa antagonists has fa iled to produce significant clinical benefit. We have examined the pharmaco logy of xemilofiban in the evaluation of oral xemilofiban in controlling th rombotic events (EXCITE) trial. The EXCITE trial was a multicenter study of xemilofiban in 7232 patients undergoing percutaneous coronary intervention . Thirty-two patients randomized to xemilofiban (10 or 20 mg three times da ily) or placebo were followed for up to 6 months. GPIIb/IIIa receptor numbe r and occupancy were quantified using two monoclonal antibodies mAb1 and mA b2. mAb1 was used to quantify receptor number. mAb2 recognizes an epitope t hat is lost due to a ligand-induced conformational change in GPIIb/IIIa and is a marker of receptor occupancy. Platelet aggregation was performed by l ight transmission. In vitro, the active metabolite of xemilofiban (SC-54701 ) inhibited mAb2 binding (IC50 of 0.5 +/- 0.1 X 10(-8) M) but not mAb1. In vivo, long-term therapy with xemilofiban did not alter GPIIb/IIIa receptor number. mAb2 binding was inhibited throughout the treatment period and reco vered slowly after drug withdrawal. Maximum inhibition of ADP-induced aggre gation occurred at 4 to 7 h after the first dose of study medication. Howev er, inhibition of platelet aggregation was low (between 24 and 45%) before dosing on days 60 and 180. There was no significant rebound increase in pla telet aggregation after drug withdrawal. Long-term xemilofiban therapy does not alter platelet GPIIb/IIIa receptor number. Inhibition of platelet aggr egation was poor at the end of each dosing interval and this may explain th e failure of xemilofiban to alter clinical events.