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

FARMACI ANTICOAGULANTI

J.W. Eikelboom, Circulation 2010

ANTICOAGULANTI ORALI

VAO Vecchi Anticoagulanti Orali

AVK

Anti Vitamina K

NOA Nuovi Anticoagulanti Orali

AOD Anticoagulanti Orali Diretti

DOA: MECCANISMO D’AZIONE

XIIa XIa

IXa

Xa

IIa

VIIa

Fibrinogeno Fibrina

VIIIa

Va

inibitori FXa inibitori FIIa

warfarin

CARATTERISTICHE DEI FARMACI ANTICOAGULANTI AD AZIONE

DIRETTA

ORIGINE SINTETICA

RAPIDO INIZIO

SELETTIVITA’ D’AZIONE

CONFEZIONE ORIGINALE DEL WARFARIN

Warfarin

sintesi di fattori emostatici NON

FUNZIONANTI

Antagonism of

Vitamin K

TAO: MECCANISMO D’AZIONE

Vitamin K

VII IX X II

Daily Dose Daily Dose

Maintenance Dose Only

Loading Dose then Maintenance Dose

ORAL ANTICOAGULANT TARGET

SITES

Antithrombin

Fibrinogen

Factor II (Prothrombin)

Fibrin

Factor IIa (Thrombin)

Factor X

Factor IX Factor VII

Anti-FXa drugs • Apixaban • Betrixaban • Edoxaban • Rivaroxaban • LY 517717 • TAK 442 • YM 150

Anti-FIIa drugs • Dabigatran

• Ximelagatran • AZD 0837

Factor Xa

VKA drugs • Tecarfarin

• Warfarin

FVIIa

FIXa

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

AVK- DOA

Poulsen BK et al, Drugs 2011

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-MEDY

RE-NOVATE RE-SONATE

RE-NOVATE 2

RIVAROXABAN: CLINICAL DEVELOPMENT

Postsurgical prophylaxis of

DVT DVT Treatment Stroke

Prevention in AF ACS

ODIXa-KNEE EINSTEIN-DVT ROCKET-AF ATLAS ACS-TIMI 46

ODIXa-HIP EINSTEIN-EXT ROCKET-J ATLAS ACS-TIMI 51

RECORD-1 EINSTEIN-PE RECORD-2 RECORD-3

RECORD-4

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

EDOXABAN: CLINICAL DEVELOPMENT

Postsurgical prophylaxis of DVT DVT Treatment Stroke Prevention in AF

Oral direct FXa inhibition with E for thrombophylaxis after elective THR: a randomized double-blind dose-response study

The Edoxaban Hokusai-VTE Study

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

DOA

Somministrati a dosi fisse in relazione a : -breve emivita - piu’ ampia finestra terapeutica rispetto a

warfarin -minori interazioni rispetto a warfarin

FDA ANALYSIS OF RE-LY

FDA ANALYSIS OF RE-LY

FDA ANALYSIS OF ROCKET

PT AND RISK OF BLEEDING IN MAJOR ORTHOPEDIC SURGERY

(RIVAROXABAN 10mg/die)

Douxfils J et al, Thromb Res 2012

PT AND RISK OF BLEEDING IN ATRIAL FIBRILLATION

(RIVAROXABAN 20mg/die)

Douxfils J et al, Thromb Res 2012

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)

Stangier et al. Clin Pharmacokinet 2010

Stangier et al. Clin Pharmacokinet 2010

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

Kreutz R, Fundamental Clin Pharmacol 2011

Renal disease

Hepatic disease

DOA: LIVER AND RENAL FUNCTION

LIVER AND RENAL FUNCTION

POSSIAMO MISURARE LA CONCENTRAZIONE DEI DOA?

SI

DOA

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)

FARMACO CONTROLLO

Dabigatran (ng/ml) dTT aIIa

Rivaroxaban (ng/ml) aXa PT R*

Apixaban (ng/ml) aXa

* Diversa sensibilita’ dei reagenti

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….