DIFFERENTIAL DOSE-RESPONSE TO ORAL XEMILOFIBAN AFTER ANTECEDENT INTRAVENOUS ABCIXIMAB - ADMINISTRATION FOR COMPLEX CORONARY INTERVENTION

Background Placebo-controlled randomized trials of parenteral platelet glycoprotein (GP) IIb/IIIa receptor antagonists have demonstrated red uced ischemic complications of coronary angioplasty. Orally active GP IIb/IIIa blockers are being developed to allow more sustained receptor antagonism with potential for long-term secondary prevention. Sequent ial therapy with abciximab followed by an oral IIb/IIIa antagonist has not previously been reported. The clinical safety and pharmacodynamic s of a sequential therapeutic strategy are unknown. Methods and Result s Of 74 consecutive patients enrolled in a placebo-controlled, dose-ra nging pharmacokinetic/pharmacodynamic study of xemilofiban, a new oral nonpeptide GP IIb/IIIa antagonist, after elective intracoronary stent placement. 17 patients received abciximab during stent deployment as a weight-adjusted intravenous bolus and 12-hour infusion at the discre tion of the investigator. Ex vivo platelet aggregation in response to 20 mu mol/L ADP and 4 mu g/mL collagen was measured over time after th e first dose of either xemilofiban (5, 10, 15, or 20 mg) or placebo (t iclopidine) administered 8 to 18 hours after termination of abciximab and again after 1 week of twice-daily oral administration of study dru g. At baseline, patients who had received abciximab had lower platelet aggregation in response to both agonists (P<.001). A significant dose -response relationship to xemilofiban was observed. Patients who had r eceived abciximab had lower ADP-induced (P less than or equal to.010) and collagen-induced (P less than or equal to.029) platelet aggregatio n after xemilofiban. This pharmacodynamic interaction was no longer ev ident at 1 week. No significant clinical bleeding events or blood prod uct transfusions were observed in this trial. Conclusions Both the mag nitude and the duration of pharmacodynamic response to xemilofiban wer e enhanced by prior abciximab treatment. The potentiated pharmacodynam ic response was not evident after 1 week. This observation has implica tions for the safety and efficacy of sequential parenteral-oral GP IIb /IIIa blockade therapy and may be useful in deriving dose regimens for orally administered compounds.