The effect of a novel glycoprotein IIb/IIIa antagonist, SR 121566A, on platelet aggregation and activation in rhesus monkeys

SR 121566A represents a peptidomimetic glyco protein IIb/IIIa (GP IIb/IIIa) inhibitor 3-[N-{4-[4-(aminoiminomethyl)phenyl]-1,3-thiazol-2-yl}-N-(1-carb oxymethylpiperid-4-yl) amino] propionic acid, trihydrochloride. To investig ate the intravenous and subcutaneous pharmacodynamics of this agent, a prim ate model (Macaca mulatta) was used. The IC50 for adenosine diphosphate (AD P) (10 mu mol/l)-induced platelet aggregation in this primate platelet syst em was found to be 45 +/- 6 nmol/L. Comparatively in the human platelet ric h plasma system, SR 121566A demonstrated an IC50 of 39 +/- 4 nmol/L. Graded doses of SR 121566A in the range of 25-400 mug/kg were administered intrav enously. 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 12 1566A. The pharmacodynamic effects were measured by platelet aggregation us ing ADP (10 mu mol/L) as an agonist. In addition, flow cytometric methods w ere used to measure thrombin receptor-activating peptide (TRAP) (6.25 mu mo l/L)-induced platelet activation. In the subcutaneous studies, 50, 100, 250 , and 400 mug/kg of SR 121566A was administered with an identical blood-dra wing schedule and analysis as with the intravenous studies. In the intraven ous studies, all closes of SR 121566A produced > 80% inhibition of platelet aggregation 5 minutes after the administration of the drug. The duration o f 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 administratio n of both 50 and 100 mug/kg of the drug. The recovery time after the subcut aneously administered doses was found to be shorter than the intravenously administered doses. These studies demonstrate that SR 121566A is an effecti ve platelet inhibitor with predictable pharmacokinetic and pharmacodynamic characteristics.