Identification

Name
Bivalirudin
Accession Number
DB00006
Description

Bivalirudin is a synthetic 20 residue peptide (thrombin inhibitor) which reversibly inhibits thrombin. Once bound to the active site, thrombin cannot activate fibrinogen into fibrin, the crucial step in the formation of thrombus. It is administered intravenously. Because it can cause blood stagnation, it is important to monitor changes in hematocrit, activated partial thromboplastin time, international normalized ratio and blood pressure.

Type
Small Molecule
Groups
Approved, Investigational
Structure
Thumb
Weight
Average: 2180.2853
Monoisotopic: 2178.985813062
Chemical Formula
C98H138N24O33
Synonyms
  • Bivalirudin
  • Bivalirudina
  • Bivalirudinum
External IDs
  • BG-8967
  • BG8967

Pharmacology

Indication

For treatment of heparin-induced thrombocytopenia and for the prevention of thrombosis. Bivalirudin is indicated for use in patients undergoing percutaneous coronary intervention (PCI), in patients at moderate to high risk acute coronary syndromes due to unstable angina or non-ST segment elevation in whom a PCI is planned.

Associated Conditions
Contraindications & Blackbox Warnings
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Pharmacodynamics

Bivalirudin mediates an inhibitory action on thrombin by directly and specifically binding to both the catalytic site and anion-binding exosite of circulating and clot-bound thrombin. The action of bivalirudin is reversible because thrombin will slowly cleave the thrombin-bivalirudin bond which recovers the active site of thrombin.

Mechanism of action

Inhibits the action of thrombin by binding both to its catalytic site and to its anion-binding exosite. Thrombin is a serine proteinase that plays a central role in the thrombotic process, acting to cleave fibrinogen into fibrin monomers and to activate Factor XIII to Factor XIIIa, allowing fibrin to develop a covalently cross-linked framework which stabilizes the thrombus; thrombin also activates Factors V and VIII, promoting further thrombin generation, and activates platelets, stimulating aggregation and granule release.

TargetActionsOrganism
AProthrombin
inhibitor
Humans
Absorption

Following intravenous administration, bivalirudin exhibits linear pharmacokinetics. The mean steady state concentration is 12.3 +/- 1.7mcg/mL after administration of an intravenous bolus of 1mg/kg followd by a 2.5mg/kg/hr intravenous infusion given over 4 hours.

Volume of distribution

0.2L/kg

Protein binding

Other than thrombin and red blood cells, bivalirudin does not bind to plasma proteins.

Metabolism

80% proteolytic cleavage

Route of elimination

Bivalirudin is cleared from plasma by a combination of renal mechanisms (20%) and proteolytic cleavage.

Half-life
  • Normal renal function: 25 min (in normal conditions)
  • Creatinine clearance 10-29mL/min: 57min
  • Dialysis-dependant patients: 3.5h
Clearance
  • 3.4 mL/min/kg [Normal renal function]
  • 3.4 mL/min/kg [mild renal function]
  • 2.7 mL/min/kg [moderate renal function]
  • 2.8 mL/min/kg [severe renal function]
  • 1 mL/min/kg [Dialysis-dependent patients]
Adverse Effects
Learn about our commercial Adverse Effects data.
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Toxicity

Based on a study by Gleason et al., the no-observed-adverse-effect level (NOAEL) for bivalirudin, administered to rats via intravenous infusion over a 24-hour period, was 2000 mg/kg/24 h.

Affected organisms
  • Humans and other mammals
Pathways
PathwayCategory
Bivalirudin 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 Bivalirudin.
AceclofenacThe risk or severity of bleeding and hemorrhage can be increased when Aceclofenac is combined with Bivalirudin.
AcemetacinThe risk or severity of bleeding and hemorrhage can be increased when Acemetacin is combined with Bivalirudin.
AcenocoumarolThe risk or severity of bleeding can be increased when Bivalirudin is combined with Acenocoumarol.
Acetylsalicylic acidAcetylsalicylic acid may increase the anticoagulant activities of Bivalirudin.
Albutrepenonacog alfaThe therapeutic efficacy of Albutrepenonacog alfa can be decreased when used in combination with Bivalirudin.
AlclofenacThe risk or severity of bleeding and hemorrhage can be increased when Alclofenac is combined with Bivalirudin.
AldesleukinThe risk or severity of bleeding can be increased when Bivalirudin is combined with Aldesleukin.
AlemtuzumabThe risk or severity of bleeding can be increased when Bivalirudin is combined with Alemtuzumab.
AlteplaseThe risk or severity of bleeding can be increased when Bivalirudin is combined with Alteplase.
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    Severity
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    Evidence Level
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Food Interactions
  • Avoid echinacea.
  • Avoid herbs and supplements with anticoagulant/antiplatelet activity. Examples include garlic, ginger, bilberry, danshen, piracetam, and ginkgo biloba.

Products

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International/Other Brands
Angiox / Hirulog
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
AngiomaxInjection250 mg/1IntravenousSandoz Inc2019-08-01Not applicableUS flag
AngiomaxPowder, for solution250 mgIntravenousSandoz Canada Incorporated2003-05-08Not applicableCanada flag
AngiomaxInjection, powder, lyophilized, for solution250 mg/1IntravenousThe Medicines Company2000-12-15Not applicableUS flag
AngiomaxInjection, powder, lyophilized, for solution250 mg/1IntravenousCardinal Health2000-12-152014-04-30US flag
Angiomax RTUInjection, solution250 mg/1IntravenousMAIA Pharmaceuticals, Inc.2019-08-08Not applicableUS flag
BivalirudinPowder, for solution250 mgIntravenousSandoz Canada IncorporatedNot applicableNot applicableCanada flag
Bivalirudin for InjectionPowder, for solutionIntravenousFresenius Kabi2019-04-23Not applicableCanada flag
Bivalirudin in 0.9% Sodium ChlorideInjection250 mg/50mLIntravenousBaxter Healthcare Corporation2017-12-21Not applicableUS flag
Bivalirudin in 0.9% Sodium ChlorideInjection500 mg/100mLIntravenousBaxter Healthcare Corporation2017-12-21Not applicableUS flag
Bivalirudin InjectionSolutionIntravenousAvir Pharma Inc.Not applicableNot applicableCanada flag
Additional Data Available
  • Application Number
    Application Number
    Available for Purchase

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code
    Available for Purchase

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
BivalirudinInjection250 mg/1IntracavernousDr. Reddy's Laboratories Limited2017-05-31Not applicableUS flag
BivalirudinInjection250 mg/1IntravenousCipla USA Inc.2018-07-16Not applicableUS flag
BivalirudinInjection, powder, lyophilized, for solution250 mg/1IntravenousSagent Pharmaceuticals2019-01-152019-01-15US flag
BivalirudinInjection, powder, lyophilized, for solution250 mg/1IntravenousFresenius Kabi USA, LLC2016-10-28Not applicableUS flag
BivalirudinInjection, powder, lyophilized, for solution250 mg/1IntravenousSandoz Inc2015-10-23Not applicableUS flag
BivalirudinInjection, powder, lyophilized, for solution250 mg/1IntravenousAuroMedics Pharma LLC2018-07-27Not applicableUS flag
BivalirudinInjection, powder, lyophilized, for solution250 mg/1IntravenousHospira, Inc.2015-10-05Not applicableUS flag
BivalirudinInjection, powder, lyophilized, for solution250 mg/5mLIntravenousAccord Healthcare, Inc.2018-11-07Not applicableUS flag
BivalirudinInjection, powder, lyophilized, for solution250 mg/1IntravenousAthenex Pharmaceutical Division, Llc.2019-11-30Not applicableUS flag
BivalirudinInjection, powder, lyophilized, for solution250 mg/1IntravenousSandoz Inc2015-06-15Not applicableUS flag
Additional Data Available
  • Application Number
    Application Number
    Available for Purchase

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code
    Available for Purchase

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Categories

ATC Codes
B01AE06 — Bivalirudin
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as polypeptides. These are peptides containing ten or more amino acid residues.
Kingdom
Organic compounds
Super Class
Organic Polymers
Class
Polypeptides
Sub Class
Not Available
Direct Parent
Polypeptides
Alternative Parents
Hexacarboxylic acids and derivatives / Peptides / Tyrosine and derivatives / Phenylalanine and derivatives / Glutamic acid and derivatives / Asparagine and derivatives / Aspartic acid and derivatives / Isoleucine and derivatives / Leucine and derivatives / Proline and derivatives
show 22 more
Substituents
1-hydroxy-2-unsubstituted benzenoid / Alpha peptide / Alpha-amino acid amide / Alpha-amino acid or derivatives / Amine / Amino acid / Amino acid or derivatives / Amphetamine or derivatives / Aralkylamine / Aromatic heteromonocyclic compound
show 45 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
polypeptide (CHEBI:59173)

Chemical Identifiers

UNII
TN9BEX005G
CAS number
128270-60-0
InChI Key
OIRCOABEOLEUMC-GEJPAHFPSA-N
InChI
InChI=1S/C98H138N24O33/c1-5-52(4)82(96(153)122-39-15-23-70(122)92(149)114-60(30-34-79(134)135)85(142)111-59(29-33-78(132)133)86(143)116-64(43-55-24-26-56(123)27-25-55)89(146)118-67(97(154)155)40-51(2)3)119-87(144)61(31-35-80(136)137)112-84(141)58(28-32-77(130)131)113-88(145)63(42-54-18-10-7-11-19-54)117-90(147)66(45-81(138)139)110-76(129)50-107-83(140)65(44-71(100)124)109-75(128)49-106-73(126)47-104-72(125)46-105-74(127)48-108-91(148)68-21-13-38-121(68)95(152)62(20-12-36-103-98(101)102)115-93(150)69-22-14-37-120(69)94(151)57(99)41-53-16-8-6-9-17-53/h6-11,16-19,24-27,51-52,57-70,82,123H,5,12-15,20-23,28-50,99H2,1-4H3,(H2,100,124)(H,104,125)(H,105,127)(H,106,126)(H,107,140)(H,108,148)(H,109,128)(H,110,129)(H,111,142)(H,112,141)(H,113,145)(H,114,149)(H,115,150)(H,116,143)(H,117,147)(H,118,146)(H,119,144)(H,130,131)(H,132,133)(H,134,135)(H,136,137)(H,138,139)(H,154,155)(H4,101,102,103)/t52-,57+,58-,59-,60-,61-,62-,63-,64-,65-,66-,67-,68-,69-,70-,82-/m0/s1
IUPAC Name
(4S)-4-[(2S)-2-[(2S)-2-[(2S)-2-{2-[(2S)-2-(2-{2-[2-(2-{[(2S)-1-[(2S)-2-{[(2S)-1-[(2R)-2-amino-3-phenylpropanoyl]pyrrolidin-2-yl]formamido}-5-carbamimidamidopentanoyl]pyrrolidin-2-yl]formamido}acetamido)acetamido]acetamido}acetamido)-3-carbamoylpropanamido]acetamido}-3-carboxypropanamido]-3-phenylpropanamido]-4-carboxybutanamido]-4-{[(2S,3S)-1-[(2S)-2-{[(1S)-3-carboxy-1-{[(1S)-3-carboxy-1-{[(1S)-1-{[(1S)-1-carboxy-3-methylbutyl]carbamoyl}-2-(4-hydroxyphenyl)ethyl]carbamoyl}propyl]carbamoyl}propyl]carbamoyl}pyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl]carbamoyl}butanoic acid
SMILES
CC[[email protected]](C)[[email protected]](NC(=O)[[email protected]](CCC(O)=O)NC(=O)[[email protected]](CCC(O)=O)NC(=O)[[email protected]](CC1=CC=CC=C1)NC(=O)[[email protected]](CC(O)=O)NC(=O)CNC(=O)[[email protected]](CC(N)=O)NC(=O)CNC(=O)CNC(=O)CNC(=O)CNC(=O)[[email protected]@H]1CCCN1C(=O)[[email protected]](CCCNC(N)=N)NC(=O)[[email protected]@H]1CCCN1C(=O)[[email protected]](N)CC1=CC=CC=C1)C(=O)N1CCC[[email protected]]1C(=O)N[[email protected]@H](CCC(O)=O)C(=O)N[[email protected]@H](CCC(O)=O)C(=O)N[[email protected]@H](CC1=CC=C(O)C=C1)C(=O)N[[email protected]@H](CC(C)C)C(O)=O

References

Synthesis Reference

Avi Tovi, Chaim Eidelman, Shimon Shushan, Alon Hagi, Alexander Ivchenko, Gabriel-Marcus Butilca, Leah Bar-Oz, Tehila Gadi, Gil Zaovi, "Process for production of Bivalirudin." U.S. Patent US20070093423, issued April 26, 2007.

US20070093423
General References
  1. Seybert AL, Coons JC, Zerumsky K: Treatment of heparin-induced thrombocytopenia: is there a role for bivalirudin? Pharmacotherapy. 2006 Feb;26(2):229-41. [PubMed:16466327]
  2. Dager WE, Dougherty JA, Nguyen PH, Militello MA, Smythe MA: Heparin-induced thrombocytopenia: treatment options and special considerations. Pharmacotherapy. 2007 Apr;27(4):564-87. [PubMed:17381384]
  3. Dang CH, Durkalski VL, Nappi JM: Evaluation of treatment with direct thrombin inhibitors in patients with heparin-induced thrombocytopenia. Pharmacotherapy. 2006 Apr;26(4):461-8. [PubMed:16553503]
  4. Robson R: The use of bivalirudin in patients with renal impairment. J Invasive Cardiol. 2000 Dec;12 Suppl F:33F-6. [PubMed:11156732]
  5. Van De Car DA, Rao SV, Ohman EM: Bivalirudin: a review of the pharmacology and clinical application. Expert Rev Cardiovasc Ther. 2010 Dec;8(12):1673-81. doi: 10.1586/erc.10.158. [PubMed:21108549]
  6. Shammas NW: Bivalirudin: pharmacology and clinical applications. Cardiovasc Drug Rev. 2005 Winter;23(4):345-60. [PubMed:16614733]
  7. Gleason TG, Chengelis CP, Jackson CB, Lindstrom P: A 24-hour continuous infusion study of bivalirudin in the rat. Int J Toxicol. 2003 May-Jun;22(3):195-206. [PubMed:12851152]
KEGG Drug
D03136
PubChem Compound
16129704
PubChem Substance
46507415
ChemSpider
10482069
BindingDB
50248103
RxNav
60819
ChEBI
59173
ChEMBL
CHEMBL2103749
Therapeutic Targets Database
DAP000542
PharmGKB
PA10032
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Bivalirudin
AHFS Codes
  • 20:12.04.12 — Direct Thrombin Inhibitors
FDA label
Download (60.4 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedNot AvailableCoronary Artery Disease (CAD)1
4CompletedTreatmentAcute Coronary Syndromes (ACS)1
4CompletedTreatmentAcute Myocardial Infarction (AMI) / Percutaneous Coronary Intervention (PCI)1
4CompletedTreatmentAngina Pectoris / Coronary Heart Disease (CHD)1
4CompletedTreatmentCoronary Artery Disease (CAD)1
4CompletedTreatmentCoronary Heart Disease (CHD) / Myocardial Infarction1
4CompletedTreatmentNon ST Segment Elevation Myocardial Infarction (NSTEMI) / ST Segment Elevation Myocardial Infarction (STEMI)1
4CompletedTreatmentST Elevation Acute Myocardial Infarction1
4Not Yet RecruitingTreatmentEvaluate the Safety and Efficacy of Bivalirudin in Decreasing Bleeding Risk1
4Not Yet RecruitingTreatmentST Elevation Myocardial Infarction (STEMI)1

Pharmacoeconomics

Manufacturers
  • The medicines co
Packagers
  • Ben Venue Laboratories Inc.
  • Oryx Pharmaceuticals Inc.
  • Sepracor Pharmaceuticals Inc.
  • The Medicines Co.
Dosage Forms
FormRouteStrength
Injection, powder, lyophilized, for solutionIntravenous250 mg/1
Injection, solutionIntravenous250 mg/1
Injection, powder, lyophilized, for solutionIntravenous250 mg
InjectionIntracavernous250 mg/1
InjectionIntravenous250 mg/1
Injection, powder, lyophilized, for solutionIntravenous250 mg/5mL
Powder, for solutionIntravenous250 mg
Powder, for solutionIntravenous
InjectionIntravenous250 mg/50mL
InjectionIntravenous500 mg/100mL
SolutionIntravenous
Injection, solutionIntravenous5 mg/1mL
PowderIntravenous250 MG
Prices
Unit descriptionCostUnit
Angiomax 250 mg vial780.0USD vial
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US5196404No1993-03-232010-05-23US flag
CA2065150No1999-12-142010-08-17Canada flag
US7598343Yes2009-10-062029-01-27US flag
US7582727Yes2009-09-012029-01-27US flag
Additional Data Available
  • Filed On
    Filed On
    Available for Purchase

    The date on which a patent was filed with the relevant government.

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Properties

State
Solid
Experimental Properties
PropertyValueSource
Predicted Properties
PropertyValueSource
Water Solubility0.0464 mg/mLALOGPS
logP-0.76ALOGPS
logP-14ChemAxon
logS-4.7ALOGPS
pKa (Strongest Acidic)2.79ChemAxon
pKa (Strongest Basic)11.88ChemAxon
Physiological Charge-4ChemAxon
Hydrogen Acceptor Count37ChemAxon
Hydrogen Donor Count28ChemAxon
Polar Surface Area901.57 Å2ChemAxon
Rotatable Bond Count66ChemAxon
Refractivity543.33 m3·mol-1ChemAxon
Polarizability215.46 Å3ChemAxon
Number of Rings6ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.8811
Blood Brain Barrier-0.996
Caco-2 permeable-0.8319
P-glycoprotein substrateSubstrate0.8692
P-glycoprotein inhibitor INon-inhibitor0.647
P-glycoprotein inhibitor IINon-inhibitor0.7858
Renal organic cation transporterNon-inhibitor0.7959
CYP450 2C9 substrateNon-substrate0.7558
CYP450 2D6 substrateNon-substrate0.7957
CYP450 3A4 substrateSubstrate0.5794
CYP450 1A2 substrateNon-inhibitor0.8977
CYP450 2C9 inhibitorNon-inhibitor0.8331
CYP450 2D6 inhibitorNon-inhibitor0.8894
CYP450 2C19 inhibitorNon-inhibitor0.7784
CYP450 3A4 inhibitorNon-inhibitor0.744
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9357
Ames testNon AMES toxic0.7642
CarcinogenicityNon-carcinogens0.8217
BiodegradationNot ready biodegradable0.9705
Rat acute toxicity3.1654 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9307
hERG inhibition (predictor II)Non-inhibitor0.514
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Targets

Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
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. Scatena R: Bivalirudin: a new generation antithrombotic drug. Expert Opin Investig Drugs. 2000 May;9(5):1119-27. [PubMed:11060732]
  2. Bates ER: Bivalirudin for percutaneous coronary intervention and in acute coronary syndromes. Curr Cardiol Rep. 2001 Sep;3(5):348-54. [PubMed:11504570]
  3. Gladwell TD: Bivalirudin: a direct thrombin inhibitor. Clin Ther. 2002 Jan;24(1):38-58. [PubMed:11833835]
  4. Kleiman NS, Klem J, Fernandes LS, Rubin H, Challa S, Solomon S, Maresh K, Arora U, Klem E, Buergler J, Mathew S, Browning A, DeLao T: Pharmacodynamic profile of the direct thrombin antagonist bivalirudin given in combination with the glycoprotein IIb/IIIa antagonist eptifibatide. Am Heart J. 2002 Apr;143(4):585-93. [PubMed:11923794]
  5. Carswell CI, Plosker GL: Bivalirudin: a review of its potential place in the management of acute coronary syndromes. Drugs. 2002;62(5):841-70. [PubMed:11929334]
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Peroxidase activity
Specific Function
Part of the host defense system of polymorphonuclear leukocytes. It is responsible for microbicidal activity against a wide range of organisms. In the stimulated PMN, MPO catalyzes the production o...
Gene Name
MPO
Uniprot ID
P05164
Uniprot Name
Myeloperoxidase
Molecular Weight
83867.71 Da
References
  1. Rudolph V, Rudolph TK, Schopfer FJ, Bonacci G, Lau D, Szocs K, Klinke A, Meinertz T, Freeman BA, Baldus S: Bivalirudin decreases NO bioavailability by vascular immobilization of myeloperoxidase. J Pharmacol Exp Ther. 2008 Nov;327(2):324-31. doi: 10.1124/jpet.108.142414. Epub 2008 Aug 13. [PubMed:18701766]

Drug created on June 13, 2005 07:24 / Updated on November 30, 2020 13:38

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