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Characteristics of the ideal antithrombotic agent

Nuovi farmaci antitrombotici/anticoagulanti: a che punto siamo? Marco Cattaneo Clinica Medica Ospedale San Paolo – Università di Milano. Characteristics of the ideal antithrombotic agent. Potent antithrombotic effect Low risk Predictable pharmakodynamic profile, making monitoring unnecessary

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Characteristics of the ideal antithrombotic agent

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  1. Nuovi farmaci antitrombotici/anticoagulanti:a che punto siamo?Marco CattaneoClinica MedicaOspedale San Paolo – Università di Milano

  2. Characteristics of the ideal antithrombotic agent • Potent antithrombotic effect • Low risk • Predictable pharmakodynamic profile, making monitoring unnecessary • Rapid onset • Rapid offset* • Availability of an antidote • No interaction with food or adjunctive medicines commonly used • Low cost * For safety reasons, a drug with rapid offset is generally preferable to a drug with long-lasting effects, although the use of the latter might minimize the negative effects of poor compliance.

  3. Kaplan-Meier estimates of mortality during the first 30 days among patients who developed and those who did not develop major bleeding Eikelboom, J. W. et al. Circulation 2006;114:774-782

  4. “Responders” Inhibition of hemostasis (%) Thrombosis Bleeding “Non Responders” Reletionship between inhibition of platelet aggregation and the risk of thrombosis or bleeding

  5. “Responders” Inhibition of hemostasis (%) Thrombosis Bleeding “Non Responders” Days of treatment Reletionship between inhibition of platelet aggregation and the risk of thrombosis or bleeding

  6. prostacyclin agonist ADP ADP specific receptor IP receptor P2Y12 Gs Gq Gi + PI3K + AC δ cAMP + stabilization Platelet aggregation

  7. Main results of two double-blind, RANDOMIZED CLINICAL TRIALs that compared prasugrel, ticagrelor or high dose clopidogrel to standard dose clopidogrel for the treatment of patients with ACS

  8. ELINOGREL • Elinogrel is direct-acting, competitive, reversible P2Y12 non-nucleotide antagonist • IC50 ~2-3 mM in ADP aggregation (PRP) • Highly selective for P2Y12 (does not inhibit P2Y1 or other purinergic receptors) • Oral bioavailability ~50% • T1/2 ~12 h (BID drug) (Elimination: 50% renal, 50% hepatic) • Tmax 2-6 h

  9. Gurbel et al, JTH 2009

  10. ADP [mM] 1 1 1 10 10 10 Elinogrel Prasugrel Clopidogrel Relationship between inhibiiton of ADP-induced platelet aggregation and antithrombotica activity of P2Y12 inhibitors In vivo murine thrombosis model (intravital microscopy) Platelet aggregation (LTA) Clopidogrel Prasugrel Elinogrel Time to occlusion (sec) *** André et al, JPET 2011

  11. Establishment of the doses of clopidogrel, prasugrel and elinogrel providing equivalent inhibition of arterial thrombosis Clopidogrel Prasugrel Elinogrel I H M I H M I H M *** mg/kg **P<0.01;***P<0.0001 vs vehicle ctrl (V.Ctl) André et al, JPET 2011

  12. P<0.0001 P<0.0002 P=0.2124 Blood volume Loss (ml) Clopidogrel and prasugrel, but not elinogrel, increase the volume of blood loss in P2Y12-/- mice *Mouse tail transection model; MC, methyl cellulose; M, Maximal dose E, elinogrel; C, clopidogrel; P, prasugrel André et al, JPET 2011

  13. WT + clopidogrel (M) WT + Elinogrel (M) WT + V.Ctl. WT + Prasugrel (M) P2Y12-/- 0 2 4 6 8 10 12 14 16 18 20 Time (min) Thienopyridines increase bleeding frequency in venous micropuncture model to a greater extent than elinogrel (M) Maximal dose; WT=wild type mice André et al, JPET 2011

  14. Thienopyridines, but not Elinogrel, inhibit alpha,beta-2MeATP-induced vascoconstriction André et al, JPET 2011

  15. INNOVATE PCI • Phase II study to evaluate the clinical efficacy, safety, and tolerability of IV and oral elinogrel in patients undergoing nonurgent PCI • Not statistically powered for any specific endpoint • Examine a number of clinical and biological endpoints in order to develop an understanding of how elinogrel dose relates to clinical and biological efficacy, tolerability, and safety in patients undergoing non-urgent PCI • Obtain population pharmacokinetic (PK) data • Obtain pharmacodynamic (PD) data in a subset of trial participants

  16. INNOVATE PCI - AdverseEvents * Dyspnea was generally mild, transient, and infrequently led to discontinuation ^ Most cases occurred within first 60 days and were asymptomatic; All cases resolved, even when treatment was continued; No Hy’s Law cases.

  17. Dyspnea in PLATO trial

  18. Cangrelor and dyspnoea • CHAMPION PCI: a dyspnoea adverse event was reported in 1.0% of patients receiving cangrelor and 0.4% of patients receiving only clopidogrel (P = 0.001) • CHAMPION PLATFORM: a dyspnoea adverse event was reported in 1.4% of patients receiving cangrelor and 0.5% of patients receiving placebo (P = 0.002)

  19. Phase 3 Chronic CHD Trial – Sponsored by Novartis Patients with Prior MI (~24,000 pts) 6-mos to 5 yrs post-index event Background ASA PLACEBO ELINOGREL (low exposure dose) ELINOGREL (high exposure dose) Study is event driven, expected mean duration is ~29 months PRIMARY EFFICACY ENDPOINT: CV Death, MI, Stroke

  20. Coughlin, JTH 2005

  21. Synthetic analogue of himbacine LMW competitive PAR-1 antagonist Ki 2.7 nmol/L Orally available High bioavailability Hepatic and GI metabolism/escretion Modified from Becker et al, Lanect 2009

  22. Becker et al, Lancet 2009

  23. Becker et al, Lancet 2009

  24. Why PAR-1 inhibition is not associated with increased incidence of bleeding? (my guess) • Patients with severe hemophilia (in whom thrombin generation is defective) do not suffer mucocutaneous bleedings and have normal bleeding times.

  25. Why PAR-1 inhibition is not associated with increased incidence of bleeding? (my guess) • Patients with severe hemophilia (in whom thrombin generation is defective) do not suffer mucocutaneous bleedings and have normal bleeding times. • Therefore, it is possible that thrombin interaction with platelet PAR-1 does not play a major role in primary hemostasis

  26. Why PAR-1 inhibition is not associated with increased incidence of bleeding? (my guess) • Patients with severe hemophilia (in whom thrombin generation is defective) do not suffer mucocutaneous bleedings and have normal bleeding times. • Therefore, it is possible that thrombin interaction with platelet PAR-1 does not play a major role in primary hemostasis • In contrast, thrombin is the primary mediator of platelet activation within thrombi forming on diseased arteries

  27. However… (1) • Prasugrel proved to be as safe as clopidogrel in phase-II tials • Ticagrelor proved to be as safe as clopidogrel in phase-II tials

  28. However… (2) 2 brothers with mild congenital bleeding diathesis were screened for disorders of hemostasis Beate Kehler, University of Muenster, personal communication

  29. However… (2) 2 brothers with mild congenital bleeding diathesis were screened for disorders of hemostasis The only abnormality that was identified was a deficiency of the platelet PAR-1 receptors Beate Kehler, University of Muenster, personal communication

  30. Trial to Assess the Effects of SCH 530348 in Preventing Heart Attack and Stroke in Patients With Acute Coronary Syndrome (TRA•CER) (Study P04736AM2)This study has been terminated. ( The trial was terminated at the request of the Data and Safety Monitoring Board. )

  31. Trial to Assess the Effects of SCH 530348 in Preventing Heart Attack and Stroke in Patients With Atherosclerosis (TRA 2°P - TIMI 50) (Study P04737AM2)This study is ongoing, but not recruiting participants.

  32. Kogushi et al, Eur J Pharmacol 2011

  33. Kogushi et al, Eur J Pharmacol 2011

  34. Heparin and warfarin: old anticoagulants 1915 Heparin - parenteral 1939 VKA (warfarin) - oral

  35. Direct vs Indirect Anti-IIa

  36. Direct vs Indirect Anti-Xa

  37. DABIGATRAN ETEXILATE Dabigatran etexilate is an oral direct thrombin inhibitor exhibiting: Predictable anticoagulant effect Fixed dose: - No adjustment to body weight etc. Acts on clot bound and free thrombin Interference with drugs affecting P-glycoprotein (P-gp) transporter Inhibitors of P-gp (quinidine, amiodarone ) increase the plasma levels of dabigatran • Dabigatran etexilate is the pro-drug of the active compound dabigatran, which binds directly to thrombin with a high affinity and specificity

  38. Cumulative Hazard Rates for the Primary Outcome of Stroke or Systemic Embolism, According to Treatment Group. Connolly SJ et al. N Engl J Med 2009;361:1139-1151.

  39. Connolly SJ et al. N Engl J Med 2009;361:1139-1151.

  40. Characteristics of Dabigatran E. • Potent antithrombotic effect YES • Low risk YES • Predictable pharmakodynamic profile, making monitoring unnecessary YES • Rapid onset YES • Rapid offset* NO • Availability of an antidote NO • No interaction with food or adjunctive medicines commonly usedNO • Low cost NO * For safety reasons, a drug with rapid offset is generally preferable to a drug with long-lasting effects, although the use of the latter might minimize the negative effects of poor compliance.

  41. Rivaroxaban Small molecule Potent reversible fXa inhibitor Good oral bioavailability (60-80%) T1/2 life 5-9 h in younger patients 11-13 h in elderly patients Elimination: 1/3 (unchanged ) renal clearance 1/3 in the liver (CYP), metabolites excreted in the feces 1/3 in the liver, metabolites excreted by the kidneys

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