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Campagna Educazionale Nazionale ANMCO 2014 METEORITI SFIDARE L’ICTUS NELLA FIBRILLAZIONE ATRIALE

Campagna Educazionale Nazionale ANMCO 2014 METEORITI SFIDARE L’ICTUS NELLA FIBRILLAZIONE ATRIALE. CARATTERISTICHE FARMACOLOGICHE DEI NUOVI ANTICOAGULANTI ORALI. New Anticoagulants. Coagulation cascade. Drug. Tissue factor pathway inhibitors: NAPc2. TF/VIIa. Initiation. X. IX. IXa.

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Campagna Educazionale Nazionale ANMCO 2014 METEORITI SFIDARE L’ICTUS NELLA FIBRILLAZIONE ATRIALE

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  1. Campagna Educazionale Nazionale ANMCO 2014 METEORITI SFIDARE L’ICTUS NELLA FIBRILLAZIONE ATRIALE CARATTERISTICHE FARMACOLOGICHE DEI NUOVI ANTICOAGULANTI ORALI

  2. New Anticoagulants • Coagulationcascade • Drug Tissue factor pathway inhibitors:NAPc2 • TF/VIIa • Initiation • X • IX • IXa • VIIa Indirect: fondaparinux, idraparinux Direct Oral: rivaroxaban, apixaban, edoxaban • Propagation • Xa • Va • II • Thrombin activity Direct Parenteral: bivalirudin Direct Oral: ximelagatran, dabigatran, AZD0837 • IIa • Fibrinogen • Fibrin

  3. New Anticoagulants

  4. CharacteristicsofNOACscomparedwithVKAs

  5. PK/PD of Novel Oral Anticoagulants CYP = cytochrome P450; NR = not reported Ruff CR and Giugliano RP. Hot Topics in Cardiology 2010;4:7-14 Ericksson BI et al. Clin Pharmacokinet 2009; 48: 1-22 Ruff CR et al. Am Heart J 2010; 160:635-41

  6. Atrial Fibrillation Phase 3 Study Timelines Edoxaban Rivaroxaban Dabigatran ENGAGE AF TIMI 48 Published November 2013 ROCKET AF Published August 2011 RE-LY Published 2009 2009 2010 2011 2012 2013 AVERROES Published February 2011 ARISTOTLE Published August 2011 Apixaban

  7. Dabigatran etexilate

  8. Oral prodrug, converted to dabigatran, a potent reversible direct thrombin inhibitor (DTI) Half life of 12-17 h, ~ 80% renally excreted 6.5% bioavailability Rapid onset of action Predictable and consistent anticoagulant effects Low potential for drug-drug interactions, no drug-food interactions No requirement for routine coagulation monitoring Potent antithrombotic effects are achieved with direct thrombin inhibitors by specifically blocking the activity of thrombin (both free and clot-bound), the central enzyme in the process responsible for clot (thrombus) formation Dabigatran etexilate: a novel direct thrombin inhibitor Stangier J et al British Journal of Clinical Pharmacology 2007, DOI:10.1111/j.1365-2125.2007.02899. Sorbera LA et al Dabigatran/Dabigatran Etexilate Drugs of the Future 2005; 30 (9): 877-885. Belch S et al. DMB 2007; doi:10.1124/dmb.107.019083

  9. The capsule formulation of dabigatran etexilate Capsule Pellet Tartaric acid core Seal coating Dabigatran etexilate coat Generation of acidic microenvironment by tartaric acid core  Increase of drug dissolution and absorption  Ensures that absorption is less affected by variations in gastric pH Disclaimer: Dabigatran etexilate is now approved for clinical use in stroke prevention in atrial fibrillation in certain countries. Please check local prescribing information for further details. Dec 2011

  10. What is P-glycoprotein and how does it work? P-gp = P-glycoprotein Adapted from Lin J. Adv Drug Deliv Rev 2003;55:53–81 Intestinal apical cell Drug P-gp Bloodcirculation Gastrointestinal lumen Metab Disclaimer: Dabigatranetexilate is now approved for clinical use in stroke prevention in atrial fibrillation in certain countries. Please check local prescribing information for further details. Dec 2011

  11. Dabigatran etexilate and P-glycoprotein P-gp = P-glycoprotein Adapted from Lin J. Adv Drug Deliv Rev 2003;55:53–81 Intestinal apical cell Dabigatran P-gp Dabigatran plasma level Metab Gastrointestinal lumen Blood circulation High concentrations of a strong P-gp inhibitor in the gut at the time dabigatran is ingested can lead to increased systemic delivery of dabigatran as the P-gp-mediatedefflux of dabigatran back into the gut is blocked Disclaimer: Dabigatranetexilate is now approved for clinical use in stroke prevention in atrial fibrillation in certain countries. Please check local prescribing information for further details. Dec 2011

  12. Haemodialysis Stangier J et al. Clin Pharmacokinet 2010;49:259–68 25 Patient 1 Patient 2 Patient 3 20 Patient 4 Patient 5 15 Patient 6 Dabigatran concentration (ng/mL) 10 5 0 Inlet Outlet Inlet Outlet Inlet Outlet 0.5 hrs 2 hrs 4 hrs Plasma concentration of total dabigatran in the dialyser inlet and outlet lines after oral administration of 50 mg dabigatran to patients with end-stage renal disease Disclaimer: Dabigatranetexilate is now approved for clinical use in stroke prevention in atrial fibrillation in certain countries. Please check local prescribing information for further details. • Haemodialysis removes ~62% of dabigatran at 2 hoursand ~68% at 4 hours Dec 2011

  13. Rivaroxaban

  14. Rivaroxaban: the first in class oral, direct FXa inhibitor • Direct, specific, competitive FXa inhibitor • Inhibits free and fibrin-bound FXa activity, and prothrombinase activity • Effective anticoagulant • Inhibits thrombin generation – acts earlier in the coagulation cascade • No direct effect on platelet aggregation • Effects can potentially be reversed by recombinant Factor VIIa, if required Perzborn et al., J Thromb Haemost 2005; Pathophysiol Haemost Thromb 2004; Depasse et al., J Thromb Hameost 2005;Kubitza et al.,Clin Pharmacol Ther 2005;Br J Clin Pharmacol 2007;Eur J Clin Pharmacol 2005; Graff et al., J Clin Pharmacol 2007; Fareed et al., J Thromb Haemost 2005; Tinel et al., Blood 2006

  15. Rivaroxaban dosing: overlap between od and bid regimens Maximum (Cmax) and minimum (Ctrough) rivaroxaban plasma concentrations in the bid and od studies, with 25th and 75th percentiles (horizontal lines) and 5th and 95th percentiles (circles) 120 400 bid study bid study od study od study 100 300 80 Rivaroxaban Ctrough (μg/l) 60 Rivaroxaban Cmax (μg/l) 200 40 100 20 0 0 5 10 15 20 5 10 15 20 Rivaroxaban daily dose (mg) Rivaroxaban daily dose (mg) Cmax Ctrough Mueck et al,2008

  16. Apixaban

  17. O N NH2 N N O O O N Apixaban: a novel direct factor Xa inhibitor Apixaban, a structurally novel and neutral bicyclic pyrazole, was rationally designed and selected for the following qualities: • Not a prodrug • Oral bioavailability: ~50% • Tmax: 3–4 h • ~87% boundto plasma proteins • T1/2: ~12 h • Multiple elimination/excretion pathways: ~27% renally excreted • No active circulating metabolites Apixaban • Apixaban SmPC 2012 • Pinto et al. J Med Chem. 2007 Nov 1;50(22):5339-56 T1/2 = elimination half-life; Tmax = time to reach maximum plasma concentration

  18. Apixaban eliminated from the body via multiple routes Only ~27% of apixaban is eliminated by the kidneys Liver metabolism Biliary elimination Direct intestinal excretion Renal elimination (27%) Unchanged apixaban is the major drug-related component in human plasma with no active circulating metabolites present Apixaban SmPC 2012

  19. The apixaban 5 mg BD regimen demonstrates a lower peak:trough ratio compared with apixaban 10 mg OD Mean plasma concentration following multiple oral doses 5 mg BD 10 mg OD Apixaban concentration (ng/mL) Time (h) Frost et al. J Thromb Haemost 2007; 5 Supplement 2: P-M-664. Data on File API-001

  20. Impact of intrinsic factors on apixaban pharmacokinetics Fold change relative to reference and 90% CI Population description Severe renal impairment1 (CrCl: 15-29 mL/min) Moderate renal impairment1 (CrCl: 30-50 mL/min) Mild renal impairment1 (CrCl: 51-80 mL/min) Age ≥65 years2 PK Cmax Body weight ≥120 kg3 AUC Body weight ≤50 kg3 Moderate hepatic impairment4 (Child-Pugh A) Mild hepatic impairment4 (Child-Pugh B) Female gender2 0.0 0.5 1.0 1.5 2.0 2.5 3.0 1. Chang et al. CPDD 2012;1:185-186, abstract no.1381212. 2. Frost  et al. J Thromb Haemost 2009;7(Suppl 2):PP-MO-407. 3. Upreti et al. J Clin Pharmacol 2010;50:1060., abstract no.16. 4. Frost et al. Clin Pharmacol Ther 2009;85(Suppl 1):S34: abstract no.PI-84. 4. Data on File API-002

  21. Use of reduced dose of various new oral anticoagulants in AF patients CrCl: creatinine clearance The information in this table is based on the SmPC’s for apixaban, rivaroxaban and dabigatran. Please refer to the individual SmPC’s for further information. 1. Apixaban SmPC 2012. 2. Rivaroxaban SmPC 2012. 3. Dabigatran SmPC 2012

  22. Selection of appropriate NOACs for AF patients Gong IY et al. Canadian J Cardiol 2013;29:S24-S33

  23. 29 RCTs evaluating 152 116 patients (mean follow-up of 16 months) • NOACs not associated with an increased risk of drug-induced liver injury • (RR 0.90, 95% CI 0.72 to 1.13) • - similar results obtained for individual NOAC (rivaroxaban, apixaban, dabigatran, • darexaban, edoxaban) • risk of transaminases elevations (>3×ULN) lower among NOAC-treated patients, • in particular in comparison with LMWH-treated patients (RR 0.71, 95% CI 0.59 to 0.85) Caldeira D et al. Heart 2014, published on January 29

  24. Interazioni farmacologiche

  25. Interazioni farmacologiche: farmacocinetiche

  26. Drug Interactions of NOACs EHRA Practical Guide, Europace 2013:15: 625-51

  27. Interazioni farmacologiche: farmacodinamiche

  28. Alexander JH et al. Eur Heart J 2014;35:224-32

  29. BID = twice daily; BP = blood pressure; HR = hazard ratio; CI = confidence interval; TIA = transient ischaemic attack Dans AL et al. Presented at ESC 2011; Session 709009 – 709010

  30. Eikelboom JW et al. Circulation 2011;123:2363-72

  31. Alexander JH et al. Eur Heart J 2014;35:224-32

  32. Alexander JH et al. Eur Heart J 2014;35:224-32

  33. Alexander JH et al. Eur Heart J 2014;35:224-32

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