I NUOVI ANTICOAGULANTI ORALI MECCANISMO D AZIONE E FARMACOLOGIA

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Geraldina Filippi
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1 I NUOVI ANTICOAGULANTI ORALI MECCANISMO D AZIONE E FARMACOLOGIA SOPHIE TESTA CENTRO EMOSTASI E TROMBOSI LABORATORIO ANALISI CHIMICO-CLINICHE E MICROBIOLOGICHE Istituti Ospitalieri di Cremona

2 FARMACI ANTICOAGULANTI J.W. Eikelboom, Circulation 2010

3 ANTICOAGULANTI ORALI VAO Vecchi Anticoagulanti Orali NOA Nuovi Anticoagulanti Orali AVK Anti Vitamina K AOD Anticoagulanti Orali Diretti

4 DOA: MECCANISMO D AZIONE XIIa XIa IXa inibitori FXa VIIIa Xa VIIa warfarin Va inibitori FIIa Fibrinogeno IIa Fibrina

5 CARATTERISTICHE DEI FARMACI ANTICOAGULANTI AD AZIONE DIRETTA ORIGINE SINTETICA RAPIDO INIZIO SELETTIVITA D AZIONE

6 CONFEZIONE ORIGINALE DEL WARFARIN

7 TAO: MECCANISMO D AZIONE Vitamin K Antagonism of Vitamin K sintesi di fattori VII emostatici NON IX FUNZIONANTI X II Warfarin

8 Loading Dose then Maintenance Dose Daily Dose Maintenance Dose Only Daily Dose

9 ORAL ANTICOAGULANT TARGET SITES Factor IX Factor VII Factor X FVIIa Anti-FXa drugs Apixaban Betrixaban Edoxaban Rivaroxaban LY TAK 442 YM 150 FIXa Factor Xa Antithrombin VKA drugs Tecarfarin Warfarin Factor II (Prothrombin) Factor IIa (Thrombin) Anti-FIIa drugs Dabigatran Ximelagatran AZD 0837 Fibrinogen Fibrin

Factor Xa Antithrombin VKA drugs Tecarfarin Warfarin Factor II (Prothrombin)

10 FARMACOCINETICA E FARMACODINAMICA FARMACOCINETICA: assorbimento, distribuzione, metabolismo, escrezione FARMACODINAMICA: effetti biochimici e funzionali del farmaco e il meccanismo d azione 1) siti d azione del farmaco 2) relazione tra dose del farmaco e risposta funzionale

biochimici e funzionali del farmaco e il meccanismo d azione 1) siti

11 AVK- DOA Poulsen BK et al, Drugs 2011

12 DABIGATRAN: CLINICAL DEVELOPMENT Postsurgical prophylaxis of DVT DVT Treatment Stroke Prevention in AF ACS RE-MODEL RE-COVER RE-LY RE-DEEM RE-MOBILIZE RE-NOVATE RE-MEDY RE-SONATE RE-NOVATE 2

13 RIVAROXABAN: CLINICAL DEVELOPMENT Postsurgical prophylaxis of DVT DVT Treatment Stroke Prevention in AF ACS ODIXa-KNEE EINSTEIN-DVT ROCKET-AF ODIXa-HIP EINSTEIN-EXT ROCKET-J ATLAS ACS-TIMI 46 ATLAS ACS-TIMI 51 RECORD-1 EINSTEIN-PE RECORD-2 RECORD-3 RECORD-4

EINSTEIN-DVT ROCKET-AF ODIXa-HIP EINSTEIN-EXT ROCKET-J ATLAS

14 APIXABAN: CLINICAL DEVELOPMENT Postsurgical prophylaxis of DVT DVT Treatment Stroke Prevention in AF ACS APROPOS Botticelli DVT ARISTOTLE APPRAISE-1 ADVANCE-1 AMPLIFY AVERROES APPRAISE-2 (study terminated because of bleeding) ADVANCE-2 AMPLIFY-EXT APPRAISE Japan ADVANCE-3

ARISTOTLE APPRAISE-1 ADVANCE-1 AMPLIFY AVERROES APPRAISE-2 (study

15 EDOXABAN: CLINICAL DEVELOPMENT Postsurgical prophylaxis of DVT Oral direct FXa inhibition with E for thrombophylaxis after elective THR: a randomized double-blind doseresponse study DVT Treatment The Edoxaban Hokusai-VTE Study Stroke Prevention in AF Randomized, parallel-group, multicenter, multinational Phase II study comparing E, an oral factor Xa inhibitor, with warfarin for SPAF STARS J-1 ENGAGE AF-TIMI 48 STARS J-2 Safety of edoxaban, an oral factor Xa inhibitor, in Asian patients with NVAF STARS E-3 STARS J-4 STARS J-5

parallel-group, multicenter, multinational Phase II study comparing E, an oral factor Xa inhibitor, with warfarin for SPAF STARS J-1

16 DOA Somministrati a dosi fisse in relazione a : -breve emivita - piu ampia finestra terapeutica rispetto a warfarin -minori interazioni rispetto a warfarin

20 FDA ANALYSIS OF RE-LY

21 FDA ANALYSIS OF RE-LY

22 FDA ANALYSIS OF ROCKET

23 PT AND RISK OF BLEEDING IN MAJOR ORTHOPEDIC SURGERY (RIVAROXABAN 10mg/die) Douxfils J et al, Thromb Res 2012

24 Douxfils J et al, Thromb Res 2012 PT AND RISK OF BLEEDING IN ATRIAL FIBRILLATION (RIVAROXABAN 20mg/die)

25 INTERAZIONI FARMACOLOGICHE Interactions should be properly evaluated. Whenever a concomitant therapy is ongoing with a drug likely to interfere with NAO, a lab control should be performed (Pengo, 2011). Many of these drugs interact with warfarin, but INR levels allows dose adjustment, which mitigates the risk of concomitant treatment (Schulman S et al, 2012)

26 Stangier et al. Clin Pharmacokinet 2010

27 Stangier et al. Clin Pharmacokinet 2010

28 INFLUENCE OF RENAL IMPAIRMENT ON THE PHARMACOKINETICS AND PHARMACODYNAMICS OF ORAL DABIGATRAN ETEXILATE: AN OPEN-LABEL, PARALLEL-GROUP, SINGLE- CENTRE STUDY Exposure to dabigatran is increased by renal impairment and correlates with the severity of renal dysfunction A decrease in the dose and/or an increase in the administration interval in these patients may be appropriate In patients with end-stage renal disease (ESRD) dabigatran can be partly removed from the plasma by haemodialysis AUC data was about two-fold greater in elderly men (> 65 years) than in young subjects after twice-daily dosing, presumably due to the 20-30% lower creatinine clearance Stangier et al. Clin Pharmacokinet 2010

29 Renal disease Hepatic disease Kreutz R, Fundamental Clin Pharmacol 2011

30 DOA: LIVER AND RENAL FUNCTION

31 LIVER AND RENAL FUNCTION

32 POSSIAMO MISURARE LA CONCENTRAZIONE DEI DOA? SI

33 DOA FARMACO CONTROLLO Dabigatran (ng/ml) Rivaroxaban (ng/ml) Apixaban (ng/ml) dtt aiia axa PT R* axa * Diversa sensibilita dei reagenti Pengo V et al, T&H 2011; Tripodi A. et al, 2012; Douxfils J et al, T&H 2012, Baglin T et al, BJH 2012, Douxfils J et al, ASH 2013 (abst)

34 CONCLUSIONI In tempi brevissimi saranno disponibili numerosi farmaci anticoagulanti orali che presentano caratteristiche differenti Hanno un meccanismo d azione selettivo e diretto contro 1 singolo fattore della coagulazione. Presentano una finestra terapeutica piu ampia rispetto ai farmaci dicumarolici e questo favorisce la somministrazione a dosi fisse giornaliere Alcune condizioni modificano la farmacocinetica e la farmacodinamica dei DOA: insuff epatica, renale, pazienti anziani, interazioni farmacologiche.

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