Differential Dose-Response to Oral Xemilofiban After Antecedent Intravenous Abciximab

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Abstract
Background Placebo-controlled randomized trials of parenteral platelet glycoprotein (GP) IIb/IIIa receptor antagonists have demonstrated reduced 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. Sequential therapy with abciximab followed by an oral IIb/IIIa antagonist has not previously been reported. The clinical safety and pharmacodynamics of a sequential therapeutic strategy are unknown. Methods and Results Of 74 consecutive patients enrolled in a placebo-controlled, dose-ranging 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 discretion of the investigator. Ex vivo platelet aggregation in response to 20 μmol/L ADP and 4 μg/mL collagen was measured over time after the first dose of either xemilofiban (5, 10, 15, or 20 mg) or placebo (ticlopidine) administered 8 to 18 hours after termination of abciximab and again after 1 week of twice-daily oral administration of study drug. 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 received abciximab had lower ADP-induced ( P ≤.010) and collagen-induced ( P ≤.029) platelet aggregation after xemilofiban. This pharmacodynamic interaction was no longer evident at 1 week. No significant clinical bleeding events or blood product transfusions were observed in this trial. Conclusions Both the magnitude and the duration of pharmacodynamic response to xemilofiban were enhanced by prior abciximab treatment. The potentiated pharmacodynamic response was not evident after 1 week. This observation has implications 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.