PHARMACOKINETICS, PHARMACODYNAMICS AND TOLERABILITY OF A POTENT, NONPEPTIDIC, GP IIB IIIA RECEPTOR ANTAGONIST FOLLOWING MULTIPLE ORAL ADMINISTRATIONS OF A PRODRUG FORM/

Po 44-3888 is a potent and selective antagonist of GP IIb/IIIa. Fol lo wing IV administration to rhesus monkeys, the (mean +/- SD.) clearance , volume of distribution and terminal half-life of Ro 44-3888 were 4.4 +/- 1.8 ml/min/kg, 0.8 +/- 0.4 l/kg and 2.5 +/- 0.8 h respectively. O ral administration of Ro 48-3657 (1 mg/kg), a doubly protected prodrug form, produced peak concentrations of Po 44-3888 (152 +/- 51 ng/ml), 4.2 +/- 2.2 h after dosing. Terminal half-life and estimated bioavaila bility were 5.1 +/- 1.6 h and 33 +/- 6% respectively. No effect on blo od pressure, heart rate or platelet counts were seen. Adenosine diphos ohate (ADP) induced platelet aggregation (PA) and cutaneous bleeding t imes (CBT) were determined prior to and after the last of 8 daily oral administrations of Ro 48-3657 (0.25 or 0.5 mg/kg) to eight rhesus mon keys. Peak and trough plasma concentrations were proportional to dose and steady state was achieved after the second administration. Inhibit ion of PA and prolongation of CBT were concentration dependent. The ex vivo IC50 (82 nM) for ADP-mediated PA correlated with a value (58 nM) determined in vitro. The CBT response curve was displaced to the righ t of the PA curve. CBT was prolonged to greater than or equal to 25 mi n when levels of Ro 44-3888 exceeded 190 nM and PA was >90% inhibited. Therefore, in rhesus monkeys, Ro 48-3657 is reproducibly absorbed and converted to its active form, is well tolerated, and has a concentrat ion-dependent effect on PA and CBT. These properties make Ro 48-3657 a n attractive candidate for evaluation in patients at high risk for art erial thrombosis.