Antithrombotic drugs direct thrombin inhibitors

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Antithrombotic drugs Direct thrombin
inhibitors These slides were kindly
provided by AstraZeneca
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Antithrombotic drugs
Fibrinolytics
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Antithrombotic drugs
Fibrinolytics
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Antithrombotic drugs
Fibrinolytics
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Antithrombotic drugs
Fibrinolytics
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Anticoagulant drugs
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Anticoagulants historical development
Dabigatran Rivaroxaban Apixaban AZD0837
Oral
Spoiled sweet clover
Warfarin clinical use
High / low dose Warfarin / INR
Ximelagatran clinical trials
Dicoumarol discovered
Warfarin / Vitamin K mechanism
Warfarin clinical trials
1916
1924
1936
1940
1950s
2006
1970s
1976
1980s
1990s
2001
Heparin clinical use
LMWH discovered
Pentasaccharide clinical trials
LMWH clinical trials
Heparin discovered
Continous heparin infusion/ aPTT
Injection
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Direct thrombin inhibitors
Hirudin
Recombinant proteins
Synthetic molecules

• Derived from leech (Hirudo medicinalis)

• Recombinant hirudin (MW 6979.5 Da)
• Bivalirudin (MW 2180 Da)

• Argatroban (MW 527 Da)
• Melagatran
• Dabigatran
• AZD0837

• Polypeptide (65 amino acids)
• MW 7000 Da

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Direct thrombin inhibitors mechanism of
actionWhat can we learn from blood-sucking
animals?
Tenase complex
FIXaFVIIIa
FVIIa
Tissue factor
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Direct thrombin inhibitors mechanism of action
Thrombin
Exosite 1(fibrin bindingsite)
Argatrobanormelagatran
Active site
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Direct thrombin inhibitors mechanism of action
Thrombin
Hirudin and bivalirudin
Exosite 1(fibrin bindingsite)
Active site
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Fibrinopeptide A
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Fibrinopeptide A
Melagatran
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Melagatran
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Direct thrombin inhibitors pharmacokinetics

• Recombinant hirudin (available as lepirudin in
  the US and desirudin in Europe) has a plasma
  half-life of 40 and 120 minutes after intravenous
  and subcutaneous administration, respectively-
  The dose is monitored and adjusted to give an
  aPTT ratio of 1.5-2.5 as above this range there
  is an increased risk of bleeding- Clearance of
  hirudin is mostly renal
• Bivalirudin, which is only administered
  intravenously, has a half-life of approximately
  25 minutes and is only partially eliminated by
  the kidneys
• Argatroban is administered intravenously and has
  a plasma half-life of 40-50 minutes and is
  metabolised in the liver

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Direct thrombin inhibitors major use

• For currently available intravenous direct
  thrombin inhibitors, i.e., hirudin, only
  indicated in patients with heparin induced
  thrombocytopenia and thrombosis (HIT) type II
  (decrease of thrombocytes below 100 x 109 / I and
  thrombo-embolic complications)

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Direct thrombin inhibitors major drawbacks

• All previous DTIs were administered by the
  intravenous or subcutaneous route.
• Ximelagatran was the first orally administered
  DTI, but was withdrawn because of safety concerns
• In addition, recombinant hirudin binds very
  tightly to thrombin and has been associated with
  a risk of major bleeding
• Currently available intravenous DTIs are rarely
  used in clinical practice because they provide
  limited benefits over existing agents and because
  their synthesis, by recombinant technology, is
  complex