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
NOA
Nuovi Anticoagulanti Orali
AVK
Anti Vitamina K
AOD
Anticoagulanti Orali Diretti
DOA: MECCANISMO D AZIONE
XIIa
XIa
IXa
VIIa
VIIIa
inibitori FXa
Xa
Va
inibitori FIIa
Fibrinogeno
IIa
Fibrina
warfarin
CARATTERISTICHE DEI FARMACI
ANTICOAGULANTI AD AZIONE
DIRETTA
ORIGINE SINTETICA
RAPIDO INIZIO
SELETTIVITA D AZIONE
CONFEZIONE ORIGINALE DEL
WARFARIN
TAO:
MECCANISMO D’AZIONE
Vitamin K
Antagonism
of
Vitamin K
sintesi di fattori
VII emostatici
NON
IX FUNZIONANTI
X
II
Warfarin
Loading Dose then
Maintenance Dose
Daily Dose
Maintenance
Dose Only
Daily Dose
ORAL ANTICOAGULANT TARGET
SITES
Factor IX
Factor VII
Factor X
Anti-FXa drugs
FVIIa
VKA drugs
FIXa
• Apixaban
• Betrixaban
• Edoxaban
• Rivaroxaban
• LY 517717
• TAK 442
• YM 150
• Tecarfarin
• Warfarin
Factor Xa
Antithrombin
Anti-FIIa drugs
Factor II
(Prothrombin)
Fibrinogen
• Dabigatran
• Ximelagatran
• AZD 0837
Factor IIa
(Thrombin)
Fibrin
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
RE-MODEL
RE-COVER
RE-MOBILIZE
RE-MEDY
RE-NOVATE
RE-SONATE
RE-NOVATE 2
Stroke Prevention
in AF
RE-LY
ACS
RE-DEEM
RIVAROXABAN:
CLINICAL DEVELOPMENT
Postsurgical
prophylaxis of
DVT
DVT Treatment
Stroke
Prevention in AF
ACS
ODIXa-KNEE
EINSTEIN-DVT
ROCKET-AF
ATLAS
ODIXa-HIP
EINSTEIN-EXT
ROCKET-J
RECORD-1
EINSTEIN-PE
RECORD-2
RECORD-3
RECORD-4
ACS-TIMI 46
ATLAS
ACS-TIMI 51
APIXABAN:
CLINICAL DEVELOPMENT
Postsurgical
prophylaxis of
DVT
DVT Treatment
APROPOS
Botticelli DVT
ADVANCE-1
AMPLIFY
ADVANCE-2
AMPLIFY-EXT
ADVANCE-3
Stroke
Prevention in AF
ARISTOTLE
AVERROES
ACS
APPRAISE-1
APPRAISE-2 (study
terminated because of
bleeding)
APPRAISE Japan
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
STARS E-3
STARS J-4
STARS J-5
inhibitor, in Asian patients with NVAF
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
Renal disease
Hepatic
disease
Kreutz R, Fundamental Clin Pharmacol 2011
DOA: LIVER AND RENAL
FUNCTION
LIVER AND RENAL FUNCTION
POSSIAMO MISURARE LA
CONCENTRAZIONE DEI DOA?
SI
DOA
FARMACO
CONTROLLO
Dabigatran (ng/ml)
dTT
aIIa
Rivaroxaban (ng/ml)
aXa
PT R*
Apixaban (ng/ml)
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)
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….