Background:
TRA-PCI was a multicenter, randomized, double-blind, placebo-controlled study demonstrating the safety of SCH 530348, a potent thrombin receptor antagonist (TRA), in patients undergoing non-urgent percutaneous coronary intervention (PCI). A secondary endpoint in a sub-study within the primary evaluable patient cohort was inhibition of platelet aggregation (IPA) induced by appropriate agonists relative to baseline. We hypothesized that TRA therapy would selectively inhibit platelet aggregation induced by the thrombin receptor agonist peptide (TRAP) and that sustained inhibition would be observed. Pharmacokinetic (PK) studies were also carried out.
Methods:
Platelet aggregation responses to TRAP, adenosine diphosphate (ADP), collagen and arachidonic acid (AA) were measured using light transmission aggregometry (LTA) at baseline, 30, 60, 90, 120 min following a loading dose (10, 20 or 40 mg vs placebo) and after a maintenance dose (0.5, 1.0 or 2.5 mg/day) at 30 and 60 days. PK was assessed at 30 and 60 min and 2 hr after loading dose administration.
Results:
TRA was active in inhibiting 15 μM TRAP-induced platelet aggregation with onset of inhibition directly related to dose. Loading doses of 10, 20 or 40 mg achieved >90% inhibition of platelet aggregation (IPA) 60 –120 min post dose with the 40 mg dose achieving >90% inhibition between 60 and 90 min. Patients receiving maintenance doses of 0.5, 1.0 or 2.5 mg exhibited >90% IPA at 30 and 60 days. Placebo treated patients had on average ≥10% IPA to TRAP. TRA had no significant effects on ADP, collagen or AA -induced platelet aggregation compared with placebo controls. TRA PK was characterized by fast distribution and slow elimination (t1/2 = 165–311 hr) with clear evidence of hysteresis.
Conclusion:
Among PCI patients treated with TRA, there was a specific, dose-related, sustained inhibition of TRAP-induced platelet aggregation, without an impact on other aggregation related pathways. These data suggest that TRA is a potent, selective inhibitor of PAR-1 activity induced by thrombin activation of platelets, and, in view of this, is a promising therapeutic utility for treatment of thrombosis.
Inhibitory effects of FR171113, a novel, thrombin receptor antagonist, on platelet aggregation and thrombosis model in guinea-pigs