Thrombin Receptor Antagonists
Thrombin is a protease that plays an important role in coagulation. Thrombin mediates fibrin generation through hydrolytic cleavage of fibrinogen and also represents the most potent platelet agonist.[96,97] Platelet responses to thrombin are primarily mediated through G-protein-coupled protease-activated receptors (PARs). PARs are activated after thrombin-mediated proteolytic cleavage of their N-terminal exodomain. Platelet activation by thrombin is mediated via two PARs: PAR-1 and PAR-4. PAR-1 is the major human platelet receptor, exhibiting 10–100-times higher affinity for thrombin when compared with PAR-4. Two selective PAR-1 antagonists are under clinical evaluation: Vorapaxar (SCH530348) and Atopaxar (E5555) (Figure 2).
Vorapaxar is a synthetic tricyclic 3-phenylpyridine analog of himbacine, a natural product that has been modified as a crystalline salt for drug development and clinical use. Vorapaxar is an orally active, high-affinity, potent and competitive antagonist of PAR-1, blocking thrombin-mediated platelet activation without interfering with fibrinogen cleavage. Thus, vorapaxar does not affect the coagulation cascade or bleeding time. Furthermore, vorapaxar does not inhibit platelet activation induced by other agonists, such as ADP or collagen or by a PAR-4 agonist peptide, indicating specificity for PAR-1 inhibition.
Vorapaxar is rapidly absorbed, with high bioavailability (>90%) after oral administration. It dissociates from the PAR-1 receptor slowly, which may contribute to the prolonged pharmacodynamic effect. It presents a slow elimination with a long terminal half-life of 159–311 h. Vorapaxar is slowly but extensively metabolized, undergoing oxidation by CYP3A4. Therefore, coadministration of drugs that modify the metabolic activity of CYP3A4 such as rifampin and ketoconazole could potentially modulate vorapaxar exposure to platelets for about the half of the theorical value. The coadministration of food does not affect the overall drug efficacy.[101,103] Vorapaxar is mainly eliminated by feces and secondarily (less than 5%) by renal clearance.
Vorapaxar inhibits thrombin receptor-activating peptide (TRAP)-induced platelet aggregation in a dose-dependent manner. Of note, a 20-mg loading dose was able to achieve >80% inhibition of TRAP-induced platelet aggregation at 2 h in approximately 50% of patients. After a loading dose of 40 mg, nearly 70% of patients had >80% inhibition after 1 h and 96% after 2 h. Both 1-mg and 2.5-mg maintenance doses of vorapaxar sustained ≥80% inhibition at 30 and 60 days of treatment. Recovery of platelet function to 50% of baseline after a single dose is slow and dose dependent (1, 2 and 3 weeks after 10-, 20- and 40-mg doses, respectively). In patients dosed with 2.5 mg daily for 28 days, recovery of platelet function was observed 2–3 weeks after the last dose.[102,105]
Vorapaxar has demonstrated safety and efficacy in Phase II trials.[102,106,107] Thus, it was further evaluated in two Phase III trials. The TRA-CER trial evaluated the safety and efficacy of voarapaxar in ACS patients. According to the results of this trial, there was no clinical benefit with regard to the primary end point of the study, while an increase in the risk of major bleeding, including intracranial hemorrhage, especially in patients with prior stroke, resulted in the termination of the study. The secondary prevention study, TRA-2P-TIMI 50, has been discontinued in patients enrolled with ischemic stroke and those who experienced stroke during the trial owing to an increase in intracranial bleeding observed in these patients. Thus the study continued by enroling only patients with a history of MI or symptomatic peripheral artery disease. The results of this trial have been very recently published (please see more details in the section 'Expert commentary and five-year view').
Atopaxar is an orally active and potent PAR-1 antagonist exhibiting a slower onset of action (3.5 h) and lower half-life (23 h) compared with vorapaxar. Like vorapaxar, atopaxar is mainly metabolized by CYP3A4, and its major route of elimination is via the feces. Atopaxar has a faster recovery of platelet function after its withdrawal than vorapaxar. Preclinical studies showed anti-thrombotic effects in animal models (guinea pigs). Furthermore, atopaxar inhibits thrombin- and TRAP- induced secretion of platelet-associated inflammatory mediators, such as soluble CD40 ligand, IL-6 and P-selectin.[111,112]
Data from the Phase II studies LANCELOT-ACS and CAD[113,114] demonstrated rapid antiplatelet activity with reduced rates of ischemia and no increase in major bleeding events in the ACS group, and a trend towards decreased ischemic events in patients with CAD. However, atopaxar induced a dose-dependent increase in liver function abnormalities and QTc prolongation.[114,115] Thus, the clinical development of atopaxar has been suspended.
Overall, the PAR-1 antagonists are potent antiplatelet agents with predictable metabolic and pharmacodynamic profiles; however, their clinical efficacy and safety has raised several concerns. Thus, further studies are necessary before a conclusion is made as to whether the PAR-1 antagonists will be useful tools in the management of atherothrombosis.
Expert Rev Clin Pharmacol. 2012;5(3):319-336. © 2012 Expert Reviews Ltd.