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Nye antikoagulantia Faktor Xa-hæmmere og trombinhæmmere

Explore the development of new anticoagulants focusing on efficacy, safety, and administration convenience. Learn about the mechanisms, clinical studies, and effects of these innovative drugs.

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Nye antikoagulantia Faktor Xa-hæmmere og trombinhæmmere

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  1. Nye antikoagulantia Faktor Xa-hæmmere og trombinhæmmere LARS BORRIS OVERLÆGE ORTOPÆDKIRURGISK AFD. ÅRHUS SYGEHUS

  2. Nye antikoagulantia Initiering VF/VIIa rNAPc2 IX X fondaparinux idraparinux (razaxaban) apixaban BAY 59-7939 ……………….. ……………….. ……………….. IXa VIIIa Propagation Xa Va II Trombin aktivitet IIa (xi)melagatran dabigatran Fibrin Fibrinogen efter Weitz JI, Hirsh J. New antithrombotic drugs. Chest 2001;119:95S-107S

  3. Udvælgelseskriterier • Kirurgisk profylakse • Ikke er eller har været markedsført • Har gennemført fase II • Offentliggjorte resultater

  4. Nye antikoagulantia Initiering VF/VIIa rNAPc2 IX X BAY 59-7939 (rivaroxaban) (razaxaban) apixaban IXa VIIIa Propagation Xa Va II Trombin aktivitet IIa dabigatran Fibrin Fibrinogen efter Weitz JI, Hirsh J. New antithrombotic drugs. Chest 2001;119:95S-107S

  5. Fokusområder for udvikling af nye stoffer • Bedre effekt (VTE ) • Større sikkerhed (blødning ) • Postoperativ start • Færre administrationer (fx 1 gang ugl.) • Oral administration • Lettere styrbarhed (ingen monitorering)

  6. Standard studiedesign OP Screening K R T Dobbelt-blinding Tid (dage) Behandling Follow-up K = kontrolstof typisk LMWH T = teststof OP = THA og/eller TKA Screening: bilateral UE flebografi eller UL. AK behandling hvis PE eller DVT

  7. Standard end-points • Major VTE: alle PE* (±død), alle DVT* (± symptomer) samt død* af alle årsager • Major bleeding*: fatal blødning, blødning i kritiske organer, blødning der fører til reoperation, blødning der medfører forlængelse af indlæggelse, blødning der medfører behandlingstop *bedømt af uvildige blindede ekspertgrupper

  8. Virkningssteder for nye antikoagulantia Initiering VF/VIIa rNAPc2 IX X IXa VIIIa Propagation Xa Va II Trombin aktivitet IIa Fibrin Fibrinogen efter Weitz JI, Hirsh J. New antithrombotic drugs. Chest 2001;119:95S-107S

  9. Vævsfaktor/faktor VIIa hæmmere rNAPc2 Rekombinant nematode antikoagulant protein c2 Findes naturligt i spyttet fra hageorm (Ancylostoma caninum) Virkningsmekanisme: Hæmmer det kompleks der dannes mellem vævsfaktor og faktor VIIa i initieringsfasen Stofprofil: Halveringstid>50 timer Biotilgængelighed: 90%-100% efter sc injektion

  10. KLINISK DOKUMENTATION rNAPc2 Dose-finding studie. 293 knæalloplastik ptt. (åbent, ukontrolleret) 5 forskellige regimer: 1,5, 3 og 5 g/kg 6-12 timer PO og derefter dag 3,5 og evt. 7 1,5 eller 3 g/kg 1 time PO og derefter dag 3,5 og evt. 7 RESULTAT: 3 g/kg 1 time PO var mest effektiv med total DVT 12,2% (1,3% prox. DVT) og større blødning 2,3% Ref.:Lee A et al. Circulation 2001; 104:74-8.

  11. Virkningssteder for nye antikoagulantia Initiering VF/VIIa IX X IXa BAY 59-7939 (rivaroxaban) VIIIa Propagation Xa Va II Trombin aktivitet IIa Fibrin Fibrinogen efter Weitz JI, Hirsh J. New antithrombotic drugs. Chest 2001;119:95S-107S

  12. Direkte vs. indirekte Xa hæmmere Indirekte hæmmere er heparinerne (UFH og LMH) samt de syntetiske pentasaccarider, som hæmmer Xa via binding til antithrombin Direkte hæmmere f. eks. BAY 59 7939 hæmmer både frit Xa og bundet Xa

  13. BAY 59-7939 inhibits free FXa, prothrombinase activity, and endogenous Factor Xa in plasma Perzborn et al., ICT 2004

  14. Chemestry: BAY 59 7939 (rivaroxaban) • MW 435.89 daltons • Formula: C19H18CIN3O5S

  15. FEATURES OF BAY 59 7939 • A reversible, direct oral FXa inhibitor • Bioavailability: 60%-86% in dogs • Rapid obsorption as tablet (Cmax 2-4 h) • Intake with food increases Cmax by 40% • Half-life:5-6 h • Excretion: renal/bile

  16. 100 *** 80 ** 60 Thrombus reduction (%) 40 20 0 0.03 0.10 0.30 BAY 59-7939 (mg/kg) i.v. BAY 59-7939 has antithrombotic effects (venous thrombosis model) Venous thrombosis model – rat venous stasis model **P<0.01; ***P<0.001 Perzborn et al., ICT 2004

  17. BAY 59-7939 does not affect bleeding times at an antithrombotic-effective dose (3 mg/kg) Rat and rabbit bleeding models Data are shown as mean±SEM **P<0.01; ***P<0.001; ND = not determined Perzborn et al., ICT 2004

  18. BAY 59-7939: dose-dependent inhibition of Factor Xa Healthy human subjects

  19. Key points: pharmacodynamics In healthy human subjects, BAY 59-7939: • Dose-dependently inhibits Factor Xa • Factor Xa inhibition and plasma concentrations of BAY 59-7939 correlate strongly • Dose-dependently prolongs prothrombin time • Prothrombin time and plasma concentrations of BAY 59-7939 correlate strongly • Does not affect antithrombin or ecarin-induced thrombin (Factor IIa) activity • Prolongs time to thrombin generation, inhibits the maximum extent of thrombin generation, and the total amount of thrombin generated • Factor Xa inhibition and the maximum extent of thrombin generation show good correlation

  20. Once daily vs. twice daily dosing • Phase I studies in healthy subjects showed that single doses of rivaroxaban have pharmacodynamic effects that persist for 24 hours • Rivaroxaban significantly inhibited peak and total amounts of thrombin generated and prolonged thrombin generation time for 24 hours after dosing in healthy subjects Harder et al. Phatophysiol Haemost Thromb 2004;33:P0078 Kubitza et al. J Thromb Haemost 2005; 3: P 1704 Kubitza et al. Clin Pharmacol Ther 2005; 78: 412-21

  21. 3 Phase II bid Studies • 10942 (ODIXa-Hip – a Phase IIa Dose Escalating Proof of Principle Trial) Oral Direct Factor Xa Inhibitor BAY 59-7939 in the Prevention of VTE in Patients Undergoing Total Hip Replacement • 10944 (ODIXa-Hip IIb - bid dosing) Controlled, Double-Blind, Randomized, Dose-ranging Study on the prevention of VTE in Patients Undergoing Elective Total Hip Replacement • 10945 (ODIXa-Knee – a Phase IIb Dose-ranging Trial – bid dosing) Oral Direct Factor Xa Inhibitor BAY 59-7939 in the Prevention of VTE in Patients Undergoing Total Knee Replacement

  22. ODIXa-HIP Study (10942)(open) D1 D6-10 D+30 BAY 2.5 mg bid BAY 5 mg bid BAY 10 mg bid R BAY 20 mg bid BAY 30 mg bid BAY 30 mg od Enoxaparin THR venography Follow-up

  23. ODIXa-HIP II Study (10944)(double-blinded) D1 D6-10 D+30 BAY 2.5 mg bid BAY 5 mg bid BAY 10 mg bid R BAY 20 mg bid BAY 30 mg bid Enoxaparin THR venography Follow-up

  24. ODIXa-Knee Study (10945)(double-blinded) D1 D6-10 D+30 BAY 2.5 mg bid BAY 5 mg bid BAY 10 mg bid R BAY 20 mg bid BAY 30 mg bid Enoxaparin TKR venography follow-up

  25. Study endpoints Efficacy: evaluated 5–9 days after surgery Safety: bleeding occurring after the first dose of study drug and no later than 2 days after the last dose

  26. Results 3 bid studiesPooled analysis

  27. Efficacy: Total VTE TKA

  28. Major Bleeding

  29. Net-Clinical Benefit (in %) major VTE and major bleedings

  30. 1 Phase II odStudy • 11527 (ODIXa-OD.HIP – once daily dosing) Controlled, Double-Blind, Randomized, Dose-ranging Study of once-daily regimen of BAY 59-7939 in the Prevention of VTE in Patients Undergoing Elective Total Hip Replacement

  31. ODIXa-OD.HIP Study (11527)(double-blinded) D1 D6-10 D+30 BAY 5 mg od BAY 10 mg od BAY 20 mg od R BAY 30 mg od BAY 40 mg od Enoxaparin THR venography follow-up

  32. Dose Trend Total VTE

  33. Dose Trend Major Bleeding

  34. % major VTE major bleed 11.1 10 8.8 8.0 6.1 5.2 5 3.5 5 10 20 30 40 Enox BAY 59-7939, mg qd Net Clinical Benefit

  35. Main conclusion of dose-finding Based on efficacy results (total VTE and major VTE) and bleeding results: • Once-daily dosing in VTE-prevention seems to be benficial • Optimal dose: 10 mg od

  36. Future development programme phase III Extended Prevention of VTE in THA Short-term prevention of VTE in TKA compared with enox 40 mg od or 30 mg bid Comparison of Extended Prevention with BAY 59-7939 given for 5-6 weeks with short-term prevention with enox. in THA

  37. Virkningssteder for nye antikoagulantia Initiering VF/VIIa IX X IXa (razaxaban) apixaban VIIIa Propagation Xa Va II Trombin aktivitet IIa Fibrin Fibrinogen efter Weitz JI, Hirsh J. New antithrombotic drugs. Chest 2001;119:95S-107S

  38. FEATURES OF RAZAXABAN • Direct Factor Xa inhibitor • Oral administration

  39. Design of a phase II study in elective TKA Day 1 Day 12±2 Day 42±2 Enoxaparin 30 mg sc bid Razaxaban 25 mg po bid Razaxaban 50 mg po bid R Razaxaban 75 mg po bid Razaxaban 100 mg po bid Randomization Venography Follow-up Surgery Razaxaban initiated 6-8 h after surgery Enoxaparin initiated 12-24 h after surgery

  40. Razaxaban Enoxaparin 30 mg bid 25 mg bid 50 mg bid 100 mg bid 75 mg bid Patient characteristics N=656 n=147 n=123 n=115 n=121 n=150 Gender M/F 48 / 75 39 / 76 47 / 74 59 / 91 57 / 90 Age (years) 66 65 65 67 66 Mean and range 35-82 37-85 35-84 33-86 41-84 31 31 32 31 31 BMI 16-46 17-54 21-53 18-50 18-49 Mean and range

  41. Result Summary ITT; all evaluable patients up to day 12±2 VTE Rate Bleeding Rate 25 50 75 100 30 25 50 75 100 Razaxaban Enoxaparin Razaxaban

  42. Preferred dose:25 mg bid

  43. FUTURE DEVELOPMENTcontinues with another molecule with a more reliable absorption:apixabana phase III study in THA and TKA has already been finalized results are expected in 2006

  44. Virkningssteder for nye antikoagulantia Initiering VF/VIIa IX X IXa VIIIa Propagation Xa Va II Trombin aktivitet IIa dabigatran Fibrin Fibrinogen efter Weitz JI, Hirsh J. New antithrombotic drugs. Chest 2001;119:95S-107S

  45. Dabigatran (BIBR 953) Thrombin inhibitor • MW = 471.5 daltons Dabigatran etexilate (BIBR 1048) • MW = 627.7 daltons • Lipid water partition coefficient = 3.7

  46. Oral administration of Dabigatran etexilate 150 mg - Healthy volunteers Cmax = 2 hours T1/2 = 14 - 17 h Bioavailbility = 3-5%

  47. Study Design BISTRO IITotal Hip &Total Knee Replacement study Enoxaparin 40 mg qd 400pat Start 12 hours pre-operatively Dabigatran 50 mg bid 400 pat 150 mg bid 400 pat R Start 1-4 hours post-operatively 300 mg qd 400 pat 225 mg bid 400 pat Randomization Venography Day 6–10 Follow-up 4-6 weeks • 62 sites in 12 countries • Double-blind treatment allocation • Blinded event assessment • Central Adjudication Committee for efficacy and safety • 2000 patients - to have 1500 evaluable patients

  48. Patient Disposition 1973 Total randomised Enoxaparin Dabigatran Treatment group Randomized 1576 397 Non-treated or no surgery 19 5 1538 383 Underwent surgery 83 374 Non-evaluable VTE assessment Primary efficacy population 1164 73.9% evaluable 300 75.6% evaluable

  49. Baseline Characteristics

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