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 antagonist have demonstrated reduced ischemic complications of coronary angioplasty. Orally active GP IIb/IIIa blocker 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 xemilotiban 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 antagonists (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 duration of pharmacodynamic response to xemilotiban 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.