Interspecies comparison of the antiplatelet, antithrombotic, and hemorrhagic effects of SR 121566A, a novel nonpeptide GP IIb IIIa antagonist

We report the results from an interspecies comparison of the antiplatelet, antithrombotic, and hemorrhagic actions of SR 121566A, a novel nonpeptide a ntiplatelet agent with high affinity and specificity for the GP IIb/IIIa co mplex. SR 121566A exhibited in vitro antiplatelet activity against adenosin e diphosphate (ADP)-induced aggregation with a rank order of potency [human s = baboons = dogs] > marmosets > guinea pigs > rabbits. These in vitro fin dings were predictive for the ex vivo antiplatelet potency after i.v. admin istration of SR 121566A to dogs, guinea pigs, and rabbits [median effective dose (ED50) values, 0.02, 0.05, and 0.15 mg/kg]. The antiplatelet actions of SR 121566A translated into an acute antithrombotic effect in an arteriov enous shunt model after i.v. administration in dogs, guinea pigs, rabbits, and marmosets (ED50, 0.08, 0.10, 0.50, and 0.007 mg/kg). Hemorrhagic effect s of SR 121566A were observed in guinea pigs and rabbits at doses that repr esented 2-3 times the antithrombotic ED50, whereas in marmosets, no bleedin g was observed at the antithrombotic ED90. These results demonstrate that S R 121566A exhibits favorable actions in terms of antithrombotic potency and hemostatic safety in different animal species, suggesting that, in humans, SR 121566A will be a good candidate as an antithrombotic compound.