The Effect of a Novel Glycoprotein IIb/IIIa Antagonist,SR 121566A,on Platelet Aggregation and Activation in Rhesus Monkeys

Abstract

SR 121566A represents a peptidomimetic glycoprotein IIb/IIIa (GP IIb/IIIa) inhibitor 3-[N-{4-[4-(aminoiminomethyl)phenyl ]-1 ,3-thiazol-2-yl}-N-(1 -carboxymethylpiperid-4-yl) aminol propionic acid, trihydrochloride. To investigate the intravenous and subcutaneous pharmacodynamics of this agent, a primate model (Macaca mulatta) was used. The IC₅₀ for adenosine diphosphate (ADP) (10 μmol/L)-induced platelet aggregation in this primate platelet system was found to be 45 ± 6 nmol/L. Comparatively in the human platelet rich plasma system, SR 121566A demonstrated an IC₅₀ of 39 ± 4 nmol/L. Graded doses of SR 121566A in the range of 25-400 μg/kg were administered intravenously. Blood samples were drawn from individual groups of primates (n = 4-6) at varying periods of time up to 24 hours after administration of SR 121566A. The pharmacodynamic effects were measured by platelet aggregation using ADP (10 μmol/L) as an agonist. In addition, flow cytometric methods were used to measure thrombin receptor-activating peptide (TRAP) (6.25 μmol/L)-induced platelet activation. In the subcutaneous studies, 50, 100, 250, and 400 μg/kg of SR 121566A was administered with an identical blood-drawing schedule and analysis as with the intravenous studies. In the intravenous studies, all doses of SR 121566A produced > 80% inhibition of platelet aggregation 5 minutes after the administration of the drug. The duration of the inhibitory effect is proportional to the dose administered and the 50% recovery time ranged from 2 to 15 hours. By flow cytometry, TRAP-induced P-selectin expression was also blocked for a varying duration of time in a dose-dependent fashion. The subcutaneous studies showed >90% inhibition of platelet aggregation, which was observed at 15 minutes after administration of both 50 and 100 μg/kg of the drug. The recovery time after the subcutaneously administered doses was found to be shorter than the intravenously administered doses. These studies demonstrate that SR 121566A is an effective platelet inhibitor with predictable pharmacokinetic and pharmacodynamic characteristics.

Keywords

Antiplatelet Glycoprotein IIb/IIIa Primates Pharmacokinetics Platelet aggregation Flow cytometry.

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