Identification

Name
Bivalirudin
Accession Number
DB00006  (BTD00076, EXPT03302, BIOD00076, DB02351)
Type
Small Molecule
Groups
Approved, 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
Synonyms
  • Bivalirudina
  • Bivalirudinum
  • Hirulog
External IDs
BG-8967 / BG8967
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
AngiomaxInjection, powder, lyophilized, for solution250 mg/1IntravenousThe Medicines Company2000-12-15Not applicableUs
AngiomaxPowder, for solution250 mgIntravenousSandoz Canada Incorporated2003-05-08Not applicableCanada
AngiomaxInjection, powder, lyophilized, for solution250 mg/1IntravenousCardinal Health2000-12-152014-04-30Us
BivalirudinPowder, for solution250 mgIntravenousSandoz Canada IncorporatedNot applicableNot applicableCanada
Bivalirudin for InjectionPowder, for solution250 mgIntravenousFresenius KabiNot applicableNot applicableCanada
Bivalirudin in 0.9% Sodium ChlorideInjection250 mg/50mLIntravenousBaxter Laboratories2017-12-21Not applicableUs
Bivalirudin in 0.9% Sodium ChlorideInjection500 mg/100mLIntravenousBaxter Laboratories2017-12-21Not applicableUs
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
BivalirudinInjection250 mg/1IntracavernousDr Reddy's Laboratories2017-05-31Not applicableUs
BivalirudinInjection, powder, lyophilized, for solution250 mg/1IntravenousSandoz2015-10-23Not applicableUs
BivalirudinInjection, powder, lyophilized, for solution250 mg/5mLIntravenousMylan Institutional LLC2018-06-05Not applicableUs
BivalirudinInjection, powder, lyophilized, for solution250 mg/1IntravenousApotex Corporation2017-07-17Not applicableUs
BivalirudinInjection, powder, lyophilized, for solution250 mg/1IntravenousFresenius Kabi2017-10-30Not applicableUs
BivalirudinInjection, powder, lyophilized, for solution250 mg/1IntravenousAuro Medics Pharma Llc2018-07-27Not applicableUs
BivalirudinInjection, powder, lyophilized, for solution250 mg/1IntravenousHospira, Inc.2015-10-05Not applicableUs
BivalirudinInjection, powder, lyophilized, for solution250 mg/1IntravenousSandoz2015-06-15Not applicableUs
BivalirudinInjection, powder, lyophilized, for solution250 mg/5mLIntravenousAccord Healthcare, Inc.2018-11-07Not applicableUs
BivalirudinInjection, powder, lyophilized, for solution250 mg/1IntravenousSagent Pharmaceuticals2016-10-012018-08-10Us
International/Other Brands
Angiox
Categories
UNII
TN9BEX005G
CAS number
128270-60-0
Weight
Average: 2180.2853
Monoisotopic: 2178.985813062
Chemical Formula
C98H138N24O33
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[C@H](C)[C@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC1=CC=CC=C1)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)CNC(=O)CNC(=O)CNC(=O)CNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H]1CCCN1C(=O)[C@H](N)CC1=CC=CC=C1)C(=O)N1CCC[C@H]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

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
Pharmacodynamics

Bivalirudin 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 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
Human
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]
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
DrugInteraction
(1,2,6,7-3H)TestosteroneThe therapeutic efficacy of Bivalirudin can be increased when used in combination with (1,2,6,7-3H)Testosterone.
(R)-warfarinThe risk or severity of bleeding can be increased when Bivalirudin is combined with (R)-warfarin.
(S)-WarfarinThe risk or severity of bleeding can be increased when Bivalirudin is combined with (S)-Warfarin.
1-TestosteroneThe therapeutic efficacy of Bivalirudin can be increased when used in combination with 1-Testosterone.
18-methyl-19-nortestosteroneThe therapeutic efficacy of Bivalirudin can be increased when used in combination with 18-methyl-19-nortestosterone.
4-hydroxycoumarinThe risk or severity of bleeding can be increased when Bivalirudin is combined with 4-hydroxycoumarin.
4-HydroxytestosteroneThe therapeutic efficacy of Bivalirudin can be increased when used in combination with 4-Hydroxytestosterone.
5beta-dihydrotestosteroneThe therapeutic efficacy of Bivalirudin can be increased when used in combination with 5beta-dihydrotestosterone.
AbciximabThe risk or severity of bleeding can be increased when Bivalirudin is combined with Abciximab.
AcemetacinThe risk or severity of bleeding and hemorrhage can be increased when Bivalirudin is combined with Acemetacin.
Food Interactions
  • Dan shen, dong quai, evening primrose oil, gingko, policosanol, willow bark
  • Echinacea

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
KEGG Drug
D03136
PubChem Compound
16129704
PubChem Substance
46507415
ChemSpider
10482069
ChEBI
59173
ChEMBL
CHEMBL2103749
Therapeutic Targets Database
DAP000542
PharmGKB
PA10032
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Bivalirudin
ATC Codes
B01AE06 — Bivalirudin
AHFS Codes
  • 20:12.04.12 — Direct Thrombin Inhibitors
FDA label
Download (60.4 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentDeep Venous Thrombosis1
1Not Yet RecruitingTreatmentExtracorporeal Membrane Oxygenation Complication1
2CompletedTreatmentCardiology1
2CompletedTreatmentThrombotic events1
2Not Yet RecruitingTreatmentCoronary Heart Disease (CHD)1
3Active Not RecruitingTreatmentPeripheral Endovascular Interventions1
3CompletedPreventionHaemorrhage1
3CompletedTreatmentAcute Coronary Syndromes (ACS)1
3CompletedTreatmentCardiovascular Disease (CVD) / Coronary Artery Bypass Graft Surgery Patients2
3CompletedTreatmentCoronary Artery Bypass Graft Surgery Patients / Surgery, Cardiac1
3CompletedTreatmentHematologic Diseases1
3CompletedTreatmentMyocardial Infarction1
3CompletedTreatmentCardiac surgery, heparin-induced thrombocytopenia and thrombosis syndrome / Thrombotic events1
3RecruitingTreatmentAcute Myocardial Infarction (AMI)1
3TerminatedTreatmentAcute Myocardial Infarction (AMI)1
3TerminatedTreatmentCoronary Artery Disease1
3TerminatedTreatmentPercutaneous Coronary Intervention1
3Unknown StatusPreventionCoronary Artery Disease1
3Unknown StatusTreatmentCardiac Diseases / Coronary Artery Bypass Graft Surgery Patients / Thrombocytopenias / Thrombotic events1
4CompletedNot AvailableCoronary Artery Disease1
4CompletedPreventionCardiac surgery, heparin-induced thrombocytopenia and thrombosis syndrome / Heparin-induced Thrombocytopenia and Thrombosis Syndrome1
4CompletedTreatmentAcute Coronary Syndromes (ACS)1
4CompletedTreatmentAcute Myocardial Infarction (AMI) / Percutaneous Coronary Intervention1
4CompletedTreatmentAngina Pectoris / Coronary Heart Disease (CHD)1
4CompletedTreatmentCoronary Artery Disease1
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 RecruitingTreatmentAcute Coronary Syndromes (ACS)1
4Not Yet RecruitingTreatmentCoronary Heart Disease (CHD)1
4Not Yet RecruitingTreatmentST Elevation Myocardial Infarction (STEMI)1
4RecruitingTreatmentAcute Coronary Syndromes (ACS)1
4RecruitingTreatmentAnticoagulants / Extracorporeal Membrane Oxygenation Complication / Pediatric ALL1
4RecruitingTreatmentCoronary Artery Disease1
4RecruitingTreatmentST Elevation Myocardial Infarction (STEMI)1
4TerminatedTreatmentCoronary Artery Disease1
4Unknown StatusTreatmentCoronary Artery Disease1
4Unknown StatusTreatmentMyocardial Infarction1
4Unknown StatusTreatmentPrimary Percutaneous Coronary Intervention / ST Elevation Myocardial Infarction (STEMI)1
4WithdrawnNot AvailableCoronary Heart Disease (CHD)1
Not AvailableCompletedNot AvailableThrombin-specific Anticoagulant Bivalirudin During Percutaneous Coronary Intervention (PCI)1
Not AvailableCompletedDiagnosticCoronary Artery Disease1
Not AvailableRecruitingNot AvailableDrug Effect1

Pharmacoeconomics

Manufacturers
  • The medicines co
Packagers
  • Ben Venue Laboratories Inc.
  • Oryx Pharmaceuticals Inc.
  • Sepracor Pharmaceuticals Inc.
  • The Medicines Co.
Dosage forms
FormRouteStrength
InjectionIntracavernous250 mg/1
Injection, powder, lyophilized, for solutionIntravenous250 mg/5mL
Injection, powder, lyophilized, for solutionIntravenous250 mg/1
Powder, for solutionIntravenous250 mg
InjectionIntravenous250 mg/50mL
InjectionIntravenous500 mg/100mL
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)
US5196404No1993-03-232010-05-23Us
CA2065150No1999-12-142010-08-17Canada
US7598343Yes2009-10-062029-01-27Us
US7582727Yes2009-09-012029-01-27Us

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

Taxonomy

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
Polypeptide / Alpha peptide / Hexacarboxylic acid or derivatives / Tyrosine or derivatives / Phenylalanine or derivatives / Glutamic acid or derivatives / Asparagine or derivatives / Aspartic acid or derivatives / Leucine or derivatives / Isoleucine or derivatives
show 45 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
polypeptide (CHEBI:59173)

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 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
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 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 20, 2018 13:19