Identification

Summary

Lepirudin is a protein-based direct thrombin inhibitor used as an anticoagulant in patients with heparin-induced thrombocytopenia.

Generic Name
Lepirudin
DrugBank Accession Number
DB00001
Background

Lepirudin is a recombinant hirudin formed by 65 amino acids that acts as a highly specific and direct thrombin inhibitor.7,9 Natural hirudin is an endogenous anticoagulant found in Hirudo medicinalis leeches.7 Lepirudin is produced in yeast cells and is identical to natural hirudin except for the absence of sulfate on the tyrosine residue at position 63 and the substitution of leucine for isoleucine at position 1 (N-terminal end).4

Lepirudin is used as an anticoagulant in patients with heparin-induced thrombocytopenia (HIT), an immune reaction associated with a high risk of thromboembolic complications.3,7 HIT is caused by the expression of immunoglobulin G (IgG) antibodies that bind to the complex formed by heparin and platelet factor 4. This activates endothelial cells and platelets and enhances the formation of thrombi.4 Bayer ceased the production of lepirudin (Refludan) effective May 31, 2012.10

Type
Biotech
Groups
Approved, Withdrawn
Biologic Classification
Protein Based Therapies
Other protein based therapies
Protein Structure
Protein Chemical Formula
C287H440N80O111S6
Protein Average Weight
6979.0 Da
Sequences
>DB00001 sequence
LTYTDCTESGQNLCLCEGSNVCGQGNKCILGSDGEKNQCVTGEGTPKPQSHNDGDFEEIP
EEYLQ
References:
  1. FDA Clinical Pharmacology and Biopharmaceutics Review: Refludan (lepirudin) lyophilized powder for intravenous injection [Link]
Download FASTA Format
Synonyms
  • [Leu1, Thr2]-63-desulfohirudin
  • Desulfatohirudin
  • Hirudin variant-1
  • Lepirudin
  • Lepirudin recombinant
  • R-hirudin

Pharmacology

Indication

Lepirudin is indicated for anticoagulation in adult patients with acute coronary syndromes (ACS) such as unstable angina and acute myocardial infarction without ST elevation. In patients with ACS, lepirudin is intended for use with aspirin.7 Lepirudin is also indicated for anticoagulation in patients with heparin-induced thrombocytopenia (HIT) and associated thromboembolic disease in order to prevent further thromboembolic complications.7

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Associated Therapies
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Pharmacodynamics

Lepirudin is a recombinant hirudin that acts as a highly specific thrombin inhibitor. Its activity is measured by anti-thrombin units (ATUs) that correspond to the amount of lepirudin required to neutralize a unit of the World Health Organization α-thrombin (89/588) standard. The activity of lepirudin is 16,000 ATU/mg.7,9 A single molecule of lepirudin binds to a molecule of thrombin, blocking its thrombogenic activity. This drug increases activated partial thromboplastin time (aPTT) and PT (INR) values in a dose-dependent manner, and its mode of action is independent of antithrombin III.7,9 Platelet factor 4 does not inhibit lepirudin.7,9

The pharmacodynamic effect of lepirudin was evaluated by measuring an increase in aPTT. No saturable effect was observed at the highest tested dose (0.5 mg/kg, IV bolus).7 Thrombin time was considered an unsuitable routine test for lepirudin monitoring due to the high values detected (200 seconds) even at low doses.7 The concomitant use of thrombolytic therapy and lepirudin is not recommended due to the high risk of bleeding that may be life-threatening. In patients with a risk of bleeding, a physician should weigh the risks of lepirudin administration against its benefits. There is also an especially high risk of bleeding in patients who weigh less than 50 kg, and a lower dosage is required. Patients with renal impairment have a higher risk of hemorrhagic adverse events.7

Mechanism of action

Lepirudin is a direct thrombin inhibitor used as an anticoagulant in patients for whom heparin is contraindicated.7,3 Thrombin is a serine protease that participates in the blood-clotting cascade, and it is formed by the cleavage of pro-thrombin. Active thrombin cleaves fibrinogen and generates fibrin monomers that polymerize to form fibrin clots.5

Lepirudin binds to the catalytic and substrate-binding sites of thrombin, forming a stable, irreversible and non-covalent complex.4 This blocks the protease activity of thrombin and inhibits the coagulation process. Each molecule of lepirudin binds to a single molecule of thrombin,7 and unlike heparin, it is able to inhibit thrombin in both its clot-bound or free states.4

TargetActionsOrganism
AProthrombin
inhibitor
Humans
Absorption

Lepirudin administered as a single intravenous bolus injection of 0.4 mg/kg in 9 healthy volunteers (male and female) resulted in a Cmax of 2924 ng/mL, a tmax of 0.17 h and an AUC0-∞ of 2500 ng•h/mL.7 When 0.1, 0.15 and 0.2 mg/kg of lepirudin was administered as a single intravenous infusion over 6 hours in healthy male volunteers, lepirudin had a corresponding Cmax of 111, 203, and 2446 ng/mL and a corresponding AUC of 612, 1184, and 1446 ng•h/mL.8 Bioavailability is 100% following injection. Also, it has been reported that following subcutaneous (sc) administration, the bioavailability of lepirudin is almost 100%.4

Volume of distribution

The volume of distribution of lepirudin at steady state was 12.2 L in healthy young subjects (n=18, 18-60 years), 18.7 L in healthy elderly subjects (n=10, 65-80 years), 18.0 L in renally impaired subjects (n=16, creatinine clearance < 80 mL/min, and 32.1 L in heparin-induced thrombocytopenia patients (n=73).7 The distribution of lepirudin is mainly restricted to extracellular fluids.7

Protein binding

In human plasma, the protein binding of lepirudin was approximately 3%.7

Metabolism

As a polypeptide, lepirudin is expected to be metabolized by the sequential cleavage of amino acids by kidney exoproteases, which have carboxypeptidase and dipeptidase-like activity.7,8 The C-terminal cleavage of lepirudin aminoacids (aminoacids 1 to 65) produces four metabolites with anti-thrombotic activity: M1 (aminoacids 1 to 64), M2 (aminoacids 1 to 63), M3 (aminoacids 1 to 62), and M4 (aminoacids 1 to 61).8

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Route of elimination

Lepirudin is mostly excreted through urine (48.3%). About 35% of lepirudin is excreted unchanged, while metabolites are found in a smaller proportion (2.5% of M1, 5.4% of M2, 3.9% of M3 and 1.6% of M4).8

Half-life

Lepirudin has an initial half-life of approximately 10 minutes, and in young healthy volunteers, it has a terminal half-time of 1.3 hours.7 Lepirudin has a first-order elimination kinetic; plasma concentration increases proportionally as the lepirudin intravenous dose is increased. Elimination half-life values of up to 2 days were detected in patients with marked renal insufficiency (creatinine clearance < 15 mL/min).7

Clearance

The clearance of lepirudin is proportional to the glomerular filtration rate. On average, lepirudin clearance was 164 mL/min in healthy young subjects (n=18, 18-60 years) and 25% lower in women than in men. In healthy elderly subjects (n=10, 65-80 years), clearance was 139 mL/min, about 20% lower than in younger patients.7 This is possibly due to the lower creatinine clearance in elderly patients. In renally impaired subjects (n=16, creatinine clearance < 80 mL/min), clearance was 61 mL/min, and in heparin-induced thrombocytopenia patients (n=73), it was 114 mL/min.7

Adverse Effects
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Toxicity

The acute toxicity of intravenous lepirudin was evaluated in mice (0.1-1000 mg/kg), rats (1-1000 mg/kg), and monkeys (1-100 mg/kg), and toxicity was not detected at the doses investigated.7 The acute toxicity of lepirudin administered subcutaneously was also evaluated in mice (1-1250 mg/kg) and rats (1-500 mg/kg), and no toxicity was detected.7 One rat (100 mg/kg) died of rapid blood loss after the subcutaneous administration of lepirudin. Reactions to local injections such as hemorrhages, hematomas and/or nodules were detected in mice and rats given subcutaneous doses of lepirudin equal or higher than 500 mg/kg and 10 mg/kg, respectively.7

Chronic toxicity was evaluated in rats and monkeys given lepirudin for up to 3 months. Most of the effects observed were due to the antithrombotic action of lepirudin. After 3 months, hemosiderin deposits in the spleen and moderate sinus histiocytosis in the lymph node were observed in rats. In monkeys, external and internal hemorrhages and hematomas were detected.7 Lepidurin was reported as not mutagenic.7

Relative overdose may occur in patients with renal impairment, therefore, bolus dose and rate of infusion must be reduced in case of known or suspected renal insufficiency.7 Excessively high activated partial thromboplastin time (aPTT) values suggest an overdose and a risk of bleeding. Lepirudin has no known antidote. In case of life-threatening bleeding and if excessive plasma levels of lepirudin are suspected: 1)stop the administration of lepirudin immediately, 2) determine aPTT and coagulation parameters, 3) determine hemoglobin, and prepare for a transfusion, 4) follow the treatment guidelines for patients with shock.7 Hemofiltration or hemodialysis may be useful in case of overdose, based in single case reports and animal data.7

Pathways
PathwayCategory
Lepirudin Action PathwayDrug action
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbciximabThe risk or severity of bleeding can be increased when Abciximab is combined with Lepirudin.
AceclofenacThe risk or severity of bleeding and hemorrhage can be increased when Aceclofenac is combined with Lepirudin.
AcemetacinThe risk or severity of bleeding and hemorrhage can be increased when Lepirudin is combined with Acemetacin.
AcenocoumarolThe risk or severity of bleeding can be increased when Acenocoumarol is combined with Lepirudin.
Acetylsalicylic acidAcetylsalicylic acid may increase the anticoagulant activities of Lepirudin.
Albutrepenonacog alfaThe therapeutic efficacy of Albutrepenonacog alfa can be decreased when used in combination with Lepirudin.
AlclofenacThe risk or severity of bleeding and hemorrhage can be increased when Alclofenac is combined with Lepirudin.
AldesleukinThe risk or severity of bleeding can be increased when Lepirudin is combined with Aldesleukin.
AlemtuzumabThe risk or severity of bleeding can be increased when Lepirudin is combined with Alemtuzumab.
AlteplaseThe risk or severity of bleeding can be increased when Alteplase is combined with Lepirudin.
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Food Interactions
  • Avoid herbs and supplements with anticoagulant/antiplatelet activity. Examples include chamomile, garlic, ginger, ginkgo and ginseng.

Products

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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
RefludanPowder50 mg/1mLIntravenousBayer1998-03-062013-06-30US flag
RefludanInjection, solution, concentrate20 mgIntravenousCelgene Europe Limited2016-09-082012-07-27EU flag
RefludanInjection, solution, concentrate50 mgIntravenousCelgene Europe Limited2016-09-082012-07-27EU flag
RefludanInjection, solution, concentrate20 mgIntravenousCelgene Europe Limited2016-09-082012-07-27EU flag
RefludanPowder, for solution50 mg / vialIntravenousBayer2000-01-312013-07-26Canada flag
RefludanInjection, solution, concentrate50 mgIntravenousCelgene Europe Limited2016-09-082012-07-27EU flag

Categories

ATC Codes
B01AE02 — Lepirudin
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
Not Available
Kingdom
Organic Compounds
Super Class
Organic Acids
Class
Carboxylic Acids and Derivatives
Sub Class
Amino Acids, Peptides, and Analogues
Direct Parent
Peptides
Alternative Parents
Not Available
Substituents
Not Available
Molecular Framework
Not Available
External Descriptors
Not Available
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
Y43GF64R34
CAS number
138068-37-8

References

Synthesis Reference

Recombinant hirudin expressed by using yeast secretary (China Patent No. CN1371994A, 2001). China National Intellectual Property Administration. https://patents.google.com/patent/CN1371994A/en

General References
  1. Smythe MA, Stephens JL, Koerber JM, Mattson JC: A comparison of lepirudin and argatroban outcomes. Clin Appl Thromb Hemost. 2005 Oct;11(4):371-4. [Article]
  2. Tardy B, Lecompte T, Boelhen F, Tardy-Poncet B, Elalamy I, Morange P, Gruel Y, Wolf M, Francois D, Racadot E, Camarasa P, Blouch MT, Nguyen F, Doubine S, Dutrillaux F, Alhenc-Gelas M, Martin-Toutain I, Bauters A, Ffrench P, de Maistre E, Grunebaum L, Mouton C, Huisse MG, Gouault-Heilmann M, Lucke V: Predictive factors for thrombosis and major bleeding in an observational study in 181 patients with heparin-induced thrombocytopenia treated with lepirudin. Blood. 2006 Sep 1;108(5):1492-6. Epub 2006 May 11. [Article]
  3. Lubenow N, Eichler P, Lietz T, Greinacher A: Lepirudin in patients with heparin-induced thrombocytopenia - results of the third prospective study (HAT-3) and a combined analysis of HAT-1, HAT-2, and HAT-3. J Thromb Haemost. 2005 Nov;3(11):2428-36. [Article]
  4. Petros S: Lepirudin in the management of patients with heparin-induced thrombocytopenia. Biologics. 2008 Sep;2(3):481-90. doi: 10.2147/btt.s3415. [Article]
  5. Chapin JC, Hajjar KA: Fibrinolysis and the control of blood coagulation. Blood Rev. 2015 Jan;29(1):17-24. doi: 10.1016/j.blre.2014.09.003. Epub 2014 Sep 16. [Article]
  6. Google books [Link]
  7. Health Canada Approved Drug Products: Refludan (lepirudin) lyophilized powder for intravenous injection [Link]
  8. FDA Clinical Pharmacology and Biopharmaceutics Review: Refludan (lepirudin) lyophilized powder for intravenous injection [Link]
  9. EMA Summary of Product Characteristics: Refludan (lepirudin) powder for intravenous injection or infusion [Link]
  10. Bayer HealthCare: Discontinuation of Refludan [lepirudin (rDNA) for injection] [Link]
UniProt
P01050
KEGG Drug
D06880
PubChem Substance
46507011
RxNav
237057
ChEMBL
CHEMBL1201666
Therapeutic Targets Database
DAP000541
PharmGKB
PA450195
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Lepirudin

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4TerminatedTreatmentHeparin Induced Thrombocytopenia (HIT)1
4Unknown StatusTreatmentR-Hirudin (Thrombexx) Efficacy in Treatment of Haematomas1
4WithdrawnTreatmentHeparin Induced Thrombocytopenia (HIT)1
2CompletedTreatmentThrombotic events1
1, 2TerminatedTreatmentLung Cancers1
Not AvailableCompletedNot AvailableAcute HIT II (Heparin-induced Thrombocytopenia Type II)1

Pharmacoeconomics

Manufacturers
  • Bayer healthcare pharmaceuticals inc
Packagers
  • Bayer Healthcare
  • Berlex Labs
Dosage Forms
FormRouteStrength
Injection, powder, for suspensionIntravenous50 mg
Injection, solution, concentrateIntravenous20 mg
Injection, solution, concentrateIntravenous50 mg
PowderIntravenous
PowderIntravenous50 mg/1mL
Powder, for solutionIntravenous50 mg / vial
Prices
Unit descriptionCostUnit
Refludan 50 mg vial273.19USD vial
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US5180668No1993-01-192010-01-19US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)65 °COtto, A. & Seckler, R. Eur. J. Biochem. 202:67-73 (1991)
water solubilitySolubleHealth Canada drug label
isoelectric point3.7Health Canada drug label

Targets

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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
Curator comments
This target is a precursor of the drug's therapeutic target. Prothrombin cleaves into thrombin, which lepirudin binds to and inhibits.
General Function
Thrombospondin receptor activity
Specific Function
Thrombin, which cleaves bonds after Arg and Lys, converts fibrinogen to fibrin and activates factors V, VII, VIII, XIII, and, in complex with thrombomodulin, protein C. Functions in blood homeostas...
Gene Name
F2
Uniprot ID
P00734
Uniprot Name
Prothrombin
Molecular Weight
70036.295 Da
References
  1. Turpie AG: Anticoagulants in acute coronary syndromes. Am J Cardiol. 1999 Sep 2;84(5A):2M-6M. [Article]
  2. Warkentin TE: Venous thromboembolism in heparin-induced thrombocytopenia. Curr Opin Pulm Med. 2000 Jul;6(4):343-51. [Article]
  3. Eriksson BI: New therapeutic options in deep vein thrombosis prophylaxis. Semin Hematol. 2000 Jul;37(3 Suppl 5):7-9. [Article]
  4. Fabrizio MC: Use of ecarin clotting time (ECT) with lepirudin therapy in heparin-induced thrombocytopenia and cardiopulmonary bypass. J Extra Corpor Technol. 2001 May;33(2):117-25. [Article]
  5. Szaba FM, Smiley ST: Roles for thrombin and fibrin(ogen) in cytokine/chemokine production and macrophage adhesion in vivo. Blood. 2002 Feb 1;99(3):1053-9. [Article]
  6. Health Canada Approved Drug Products: Refludan (lepirudin) lyophilized powder for intravenous injection [Link]

Drug created at June 13, 2005 13:24 / Updated at April 30, 2022 04:55