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Girish C & M JayanthiDept of Pharmacology

JIPMER

ORAL DIRECT THROMBIN INHIBITORS

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Fibrin

Coagulation Pathway

Extrinsic pathway (Tissue factor)

Prothrombin

Thrombin

Fibrinogen

Intrinsic pathway (Contact)

X XaXaXaXa

ThrombinThrombin

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XIIXII

Contact (Eg: with glass)Contact (Eg: with glass)

XIIaXIIa

XIXI XIaXIa

IXIX IXaIXa

XX XaXa

VIIIaVIIIa

PLPL

CaCa++++

Intrinsic Pathway

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Tissue factor (TF)Tissue factor (TF)

VIIVII VIIa- TFVIIa- TF

IXIX IXaIXa

XX XaXa

XIaXIa

VIIIaVIIIa

Extrinsic Pathway

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Prothrombin

Thrombin

Fibrinogen

X XaXa

IXIX IXaIXa

VIIVII VIIa- TFVIIa- TF

Tissue factor (TF)Tissue factor (TF)

Site of Action of Drugs

HeparinWarfarin VIIIaVIIIa

VaVa

TFPI,NAPc2

-

--

-

-

--

-

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Warfarin- sole oral anticoagulant for 60 years.

Limitations-

Narrow therapeutic index

Delayed onset & offset of action

Mandatory lab monitoring

Drug interactions

Why new oral anticoagulants ?

Warfarin Therapy

Bleeding

Clotting

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Features of an ideal anticoagulant

High efficacy to safety index

Predictable dose response

Administration by parenteral and oral routes

Rapid onset of action

Availability of a safe antidote

Freedom from side effects

Minimal interactions

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Why thrombin is an excellent target?

Forms & stabilizes the clot

Further generation of thrombin

Stimulates thrombus- activated fibrinolysis inhibitor (TAFI) resulting in inhibition of fibrinolysis

Activates platelets

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Direct Thrombin Inhibitors (DTIs)

Directly binds and inhibit thrombin

Action not mediated through antithrombin

Hirudin from Hirudo medicinalis

Lepirudin – Approved for thrombosis related to Heparin Induced Thrombocytopenia (HIT)

Bivalirudin – For percutaneous coronary angioplasty

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Parenteral DTIs:

Bivalent:

Hirudin

Bivalirudin

Lepirudin

Monovalent:

Argatroban

Melagatran

Oral DTIs:

Ximelagatran

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Competitive and reversible direct thrombin inhibitor.

Inhibits thrombin activity, thrombin generation and platelet activation.

Prolongs aPTT, Prothrombin time.

No action on other serine proteases

Ximelagatran

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PharmacokineticsPharmacokinetics

Ximelagatran- MetabolitesXimelagatran- Metabolites

(Active)

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Prodrug of melagatran

About 20% of oral dose is absorbed. Tmax - 2-3 hrs, t1/2 – 4-5 hrs

Eliminated via kidney (80%)

Kinetics not influenced by sex, body weight and ethnicity

Kinetics…

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Pharmacodynamics

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Prothrombin

Thrombin

Clot bound Thrombin

Fibrinogen

Fibrin

Ximelagatran

-

-

Amplification

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Thrombin

Exosite 2

Active site

Melagatran

Exosite 1Exosite 1Fibrinogen recognition siteFibrinogen recognition site

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ThrombinThrombin

HirudinHirudin

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ThrombinThrombin

ThrombinThrombin

BivalirudinBivalirudin

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ThrombinThrombin

ThrombinThrombin

ArgatrobanArgatroban

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ThrombinThrombin

AT IIIAT III

HeparinHeparin

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Factor X aFactor X aA T IIIA T III

LMWHLMWH

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Non- hemorrhagic adverse effects:

Elevation in alanine transferase values in 6-10% patients

Developed with in 6 wks to 6 months

Normalized after discontinuation

Purpura, dizziness, edema, diarrhea, fatigue

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Drug Interactions

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Metabolism independent of CYP 450

No binding to plasma proteins or platelets

No drug- food interaction

Less propensity for drug interactions.

Interactions…

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Advantages

Administered orally at Fixed doses

Coagulation monitoring not required

Immediate action

More predictable anticoagulant response

Wider safety margin

Less inter subject variability

Minimal drug interactions

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Disadvantages:

Hepatotoxicity

No antidote available (but dialysis can hasten elimination)

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Indications & Dose

Long term secondary prevention of VTE after standard therapy for an episode of acute VTE (24mg bid)

Post operatively for the prevention of VTE after TKR surgery ( 36 mg bid)

Prevention of stroke in atrial fibrillation (36mg bid)

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Clinical trials

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SPORTIF III& IV:

Ximelagatran not inferior to warfarin for preventing stroke with no difference in bleeding rates.

METHRO III & EXPRESS:

Ximelagatran is as effective as standard therapy for VTE after major orthopaedic surgery.

THRIVE II& V:Ximelagatran is as efficacious as standard

therapy for treating DVT with similar bleeding incidents

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Current Status

NDA submitted on Dec 23, 2003

US FDA approval pending

In Europe, approved for short term orthopaedic prophylaxis.

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Conclusion

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Conclusion…

Favorable pharmacokinetic & dynamic profile

Efficacy similar to warfarin

No data in pregnancy, lactation and children

Hepatotoxicity

Benefit- risk considerations

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Will ximelagatran replace warfarin ?

Has many features of an ideal anticoagulant

Hepatotoxicity is of concern

Newer oral DTIs are being developed (Dabigatran etexilate)

If these are devoid of hepatotoxicity, it can replace warfarin

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Reviews:

1. Hirsh J, O’Donnell M, Weitz JI. New anticoagulants. Blood,2005;105:453-63.

2. Boos CJ, More RS. Anticoagulation for non-valvular atrial aibrillation – towards a new beginning with ximelagatran. Curr Control Trials Cardiovasc Med. 2004;5:3-10.

3. BrightonTA. The direct thrombin inhibitor melagatran/ximelagatran, Med J Aust 2004; 181: 432–37.

4. Kokolis S, Cavusoglu E, Clark LT, Marmur JD. Anticoagulation strategies for patients undergoing percutaneous coronary intervention: Unfractioned heparin, low- molecular- weight heparins, and direct thrombin inhibitors. Prog Cardvasc disease 2004;46: 506-23.

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Original Papers:

1. Clement B, Lopian K. Chacterization of in vitro biotransformation of new, orally active, direct thrombin inhibitor ximelagatran, an amidoxime and ester prodrug, Drug Metab Dispos 2003;31:645–51.

2. Eriksson UG, Johansson S, Attman PO, Mulec H, Frison L, Fager G, Samuelsson O. Influence of severe renal impairment on the pharmacokinetics and pharmacodynamics of oral ximelagatran and subcutaneous melagatran. Clin Pharmacokinet. 2003;42:743-53.

3. Schulman S, Wahlander K, Lundstrom T, Clason AB, Eriksson H. Secondary prevention of venous thromboembolism with the oral direct thrombin inhibitor ximelagatran. N Engl J Med 2003;349:1713-21.

4. Bredberg E, Andersson TB, Frison L, Thuresson A, Johansson S, Eriksson-Lepkowska M, Larsson M, Eriksson UG. Ximelagatran, an oral direct thrombin inhibitor, has a low potential for cytochrome P450-mediated drug-drug interactions. Clin Pharmacokinet. 2003;42:765-77.

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5. Albers GW, Diener HC, Frison L, Grind M, Nevinson M, partridge S, et al. SPORTIF Executive Steering Committee for the SPORTIF V Investigators. Ximelagatran vs warfarin for stroke prevention in patients with nonvalvular atrial fibrillation: a randomized trial. JAMA. 2005 ;293:690-8.

6. Fiessinger JN, Huisman MV, Davidson BL, Bounameaux H, Francis CW, Eriksson H, et al. THRIVE Treatment Study Investigators. Ximelagatran vs low-molecular-weight heparin and warfarin for the treatment of deep vein thrombosis: a randomized trial, JAMA.2005 ;293(6):681-9.

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Editorials:

1. Gurewich V. Ximelagatran—Promises and Concerns, JAMA 2005; 293:736-9.

2. Shapiro S S. Treating thrombosis in the 21st century. N Engl J Med 2003;18: 1762-4.

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Thank You