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Identification
NameBivalirudin
Accession NumberDB00006  (BTD00076, BIOD00076)
TypeSmall Molecule
GroupsApproved, Investigational
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.

Structure
Thumb
SynonymsNot Available
External Identifiers Not Available
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Angiomaxinjection, powder, lyophilized, for solution250 mg/1intravenousThe Medicines Company2000-12-15Not applicableUs
Angiomaxpowder for solution250 mgintravenousSunovion Pharmaceuticals Canada Inc2003-05-08Not applicableCanada
Angiomaxinjection, powder, lyophilized, for solution250 mg/1intravenousCardinal Health2000-12-15Not applicableUs
Bivalirudininjection, powder, lyophilized, for solution250 mg/1intravenousSandoz2015-06-15Not applicableUs
Bivalirudinpowder for solution250 mgintravenousSandoz Canada IncorporatedNot applicableNot applicableCanada
Bivalirudininjection, powder, lyophilized, for solution250 mg/1intravenousSandoz2015-10-23Not applicableUs
Bivalirudin for Injectionpowder for solution250 mgintravenousFresenius Kabi Canada LtdNot applicableNot applicableCanada
Approved Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Bivalirudininjection, powder, lyophilized, for solution250 mg/1intravenousHospira, Inc.2015-07-14Not applicableUs
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International Brands
NameCompany
AngioxNot Available
Brand mixturesNot Available
SaltsNot Available
Categories
UNIITN9BEX005G
CAS number128270-60-0
WeightAverage: 2180.2853
Monoisotopic: 2178.985813062
Chemical FormulaC98H138N24O33
InChI KeyOIRCOABEOLEUMC-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)[C@@H]1CCCN1C(=O)[[email protected]](CCCNC(N)=N)NC(=O)[C@@H]1CCCN1C(=O)[[email protected]](N)CC1=CC=CC=C1)C(=O)N1CCC[[email protected]]1C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(C)C)C(O)=O
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as polypeptides. These are peptides containing ten or more amino acid residues.
KingdomOrganic compounds
Super ClassOrganic Polymers
ClassPolypeptides
Sub ClassNot Available
Direct ParentPolypeptides
Alternative Parents
Substituents
  • Polypeptide
  • Alpha peptide
  • Hexacarboxylic acid or derivatives
  • N-acyl-aliphatic-alpha amino acid
  • N-acyl-alpha amino acid or derivatives
  • N-acyl-alpha-amino acid
  • Alpha-amino acid amide
  • N-acyl-l-alpha-amino acid
  • Phenylpropylamine
  • Amphetamine or derivatives
  • Alpha-amino acid or derivatives
  • N-substituted-alpha-amino acid
  • Pyrrolidine-2-carboxamide
  • Pyrrolidine carboxylic acid or derivatives
  • N-acylpyrrolidine
  • Aralkylamine
  • Phenol
  • Amino fatty acid
  • Fatty acyl
  • Benzenoid
  • N-acyl-amine
  • Fatty amide
  • Monocyclic benzene moiety
  • Tertiary carboxylic acid amide
  • Pyrrolidine
  • Tertiary amine
  • Secondary carboxylic acid amide
  • Primary carboxylic acid amide
  • Guanidine
  • Carboxamide group
  • Azacycle
  • Organoheterocyclic compound
  • Carboximidamide
  • Carboxylic acid
  • Carboxylic acid derivative
  • Carboxylic acid amide
  • Hydrocarbon derivative
  • Primary amine
  • Organooxygen compound
  • Organonitrogen compound
  • Primary aliphatic amine
  • Imine
  • Carbonyl group
  • Amine
  • Aromatic heteromonocyclic compound
Molecular FrameworkAromatic heteromonocyclic compounds
External Descriptors
Pharmacology
IndicationFor 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.
PharmacodynamicsBivalirudin directly and reversibly inhibits thrombin by specifically binding both to the catalytic site and to the 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 actionInhibits 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.
Related Articles
AbsorptionFollowing 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 bindingOther than thrombin and red blood cells, bivalirudin does not bind to plasma proteins.
Metabolism

80% proteolytic cleavage

Route of eliminationBivalirudin 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]
ToxicityBased 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
PathwayCategorySMPDB ID
Bivalirudin Action PathwayDrug actionSMP00277
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal AbsorptionNot AvailableNot Available
Blood Brain BarrierNot AvailableNot Available
Caco-2 permeableNot AvailableNot Available
P-glycoprotein substrateNot AvailableNot Available
P-glycoprotein inhibitor INot AvailableNot Available
P-glycoprotein inhibitor IINot AvailableNot Available
Renal organic cation transporterNot AvailableNot Available
CYP450 2C9 substrateNot AvailableNot Available
CYP450 2D6 substrateNot AvailableNot Available
CYP450 3A4 substrateNot AvailableNot Available
CYP450 1A2 substrateNot AvailableNot Available
CYP450 2C9 inhibitorNot AvailableNot Available
CYP450 2D6 inhibitorNot AvailableNot Available
CYP450 2C19 inhibitorNot AvailableNot Available
CYP450 3A4 inhibitorNot AvailableNot Available
CYP450 inhibitory promiscuityNot AvailableNot Available
Ames testNot AvailableNot Available
CarcinogenicityNot AvailableNot Available
BiodegradationNot AvailableNot Available
Rat acute toxicityNot AvailableNot applicable
hERG inhibition (predictor I)Not AvailableNot Available
hERG inhibition (predictor II)Not AvailableNot Available
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
Manufacturers
  • The medicines co
Packagers
Dosage forms
FormRouteStrength
Powder for solutionintravenous250 mg
Injection, powder, lyophilized, for solutionintravenous250 mg/1
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)
CA2065150 No1999-12-142010-08-17Canada
US5196404 No1993-05-232010-05-23Us
US7582727 Yes2009-01-272029-01-27Us
US7598343 Yes2009-01-272029-01-27Us
Properties
StateLiquid
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 FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
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 ]
External Links
ATC CodesB01AE06
AHFS Codes
  • 20:12.04.12
PDB Entries
FDA labelDownload (60.4 KB)
MSDSNot Available
Interactions
Drug Interactions
Drug
AbciximabAbciximab may increase the anticoagulant activities of Bivalirudin.
AcenocoumarolAcenocoumarol may increase the anticoagulant activities of Bivalirudin.
Acetylsalicylic acidAcetylsalicylic acid may increase the anticoagulant activities of Bivalirudin.
AlteplaseAlteplase may increase the anticoagulant activities of Bivalirudin.
AnistreplaseAnistreplase may increase the anticoagulant activities of Bivalirudin.
ApixabanApixaban may increase the anticoagulant activities of Bivalirudin.
ChlorotrianiseneChlorotrianisene may decrease the anticoagulant activities of Bivalirudin.
Citric AcidCitric Acid may increase the anticoagulant activities of Bivalirudin.
CollagenaseThe risk or severity of adverse effects can be increased when Bivalirudin is combined with Collagenase.
Dabigatran etexilateDabigatran etexilate may increase the anticoagulant activities of Bivalirudin.
DalteparinDalteparin may increase the anticoagulant activities of Bivalirudin.
DasatinibDasatinib may increase the anticoagulant activities of Bivalirudin.
DeferasiroxThe risk or severity of adverse effects can be increased when Bivalirudin is combined with Deferasirox.
Deoxycholic AcidThe risk or severity of adverse effects can be increased when Bivalirudin is combined with Deoxycholic Acid.
DesogestrelThe therapeutic efficacy of Bivalirudin can be decreased when used in combination with Desogestrel.
DicoumarolDicoumarol may increase the anticoagulant activities of Bivalirudin.
DydrogesteroneThe therapeutic efficacy of Bivalirudin can be decreased when used in combination with Dydrogesterone.
Edetic AcidEdetic Acid may increase the anticoagulant activities of Bivalirudin.
EdoxabanEdoxaban may increase the anticoagulant activities of Bivalirudin.
EnoxaparinEnoxaparin may increase the anticoagulant activities of Bivalirudin.
Ethyl biscoumacetateEthyl biscoumacetate may increase the anticoagulant activities of Bivalirudin.
Fondaparinux sodiumFondaparinux sodium may increase the anticoagulant activities of Bivalirudin.
GestodeneThe therapeutic efficacy of Bivalirudin can be decreased when used in combination with Gestodene.
HeparinHeparin may increase the anticoagulant activities of Bivalirudin.
HomoharringtonineThe risk or severity of adverse effects can be increased when Bivalirudin is combined with Homoharringtonine.
Ibritumomab tiuxetanThe risk or severity of adverse effects can be increased when Bivalirudin is combined with Ibritumomab.
IbrutinibThe risk or severity of adverse effects can be increased when Ibrutinib is combined with Bivalirudin.
InfliximabInfliximab may increase the anticoagulant activities of Bivalirudin.
LimaprostThe risk or severity of adverse effects can be increased when Limaprost is combined with Bivalirudin.
NintedanibThe risk or severity of adverse effects can be increased when Bivalirudin is combined with Nintedanib.
ObinutuzumabThe risk or severity of adverse effects can be increased when Bivalirudin is combined with Obinutuzumab.
Omega-3 fatty acidsOmega-3 fatty acids may increase the anticoagulant activities of Bivalirudin.
Pentosan PolysulfatePentosan Polysulfate may increase the anticoagulant activities of Bivalirudin.
PhenindionePhenindione may increase the anticoagulant activities of Bivalirudin.
PhenprocoumonPhenprocoumon may increase the anticoagulant activities of Bivalirudin.
ProgesteroneThe therapeutic efficacy of Bivalirudin can be decreased when used in combination with Progesterone.
ReteplaseReteplase may increase the anticoagulant activities of Bivalirudin.
RidogrelRidogrel may increase the anticoagulant activities of Bivalirudin.
RivaroxabanBivalirudin may increase the anticoagulant activities of Rivaroxaban.
StreptokinaseStreptokinase may increase the anticoagulant activities of Bivalirudin.
SugammadexSugammadex may increase the anticoagulant activities of Bivalirudin.
SulodexideSulodexide may increase the anticoagulant activities of Bivalirudin.
TenecteplaseTenecteplase may increase the anticoagulant activities of Bivalirudin.
TiboloneTibolone may increase the anticoagulant activities of Bivalirudin.
TipranavirTipranavir may increase the anticoagulant activities of Bivalirudin.
TositumomabThe risk or severity of adverse effects can be increased when Bivalirudin is combined with Tositumomab.
TreprostinilTreprostinil may increase the anticoagulant activities of Bivalirudin.
UrokinaseUrokinase may increase the anticoagulant activities of Bivalirudin.
Vitamin EVitamin E may increase the anticoagulant activities of Bivalirudin.
VorapaxarThe risk or severity of adverse effects can be increased when Vorapaxar is combined with Bivalirudin.
WarfarinWarfarin may increase the anticoagulant activities of Bivalirudin.
Food Interactions
  • Dan shen, dong quai, evening primrose oil, gingko, policosanol, willow bark
  • Echinacea

Targets

Kind
Protein
Organism
Human
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 homeostasis, inflammation and wound healing.
Gene Name:
F2
Uniprot ID:
P00734
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
Human
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 of hypohalous acids, primarily hypochlorous acid in physiologic situations, and other toxic intermediates that greatly enhance PMN microbicidal activity.
Gene Name:
MPO
Uniprot ID:
P05164
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 ]
Comments
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Drug created on June 13, 2005 07:24 / Updated on June 29, 2016 03:04