Identification

Summary

Icatibant is a bradykinin B2 receptor antagonist used to treat acute episodes of swelling and inflammation associated with hereditary angioedema (HAE).

Brand Names
Firazyr, Sajazir
Generic Name
Icatibant
DrugBank Accession Number
DB06196
Background

Icatibant (Firazyr) is a synthetic peptidomimetic drug consisting of ten amino acids, and acts as an effective and specific antagonist of bradykinin B2 receptors. It has been approved in the EU for use in hereditary angioedema, and is under investigation for a number of other conditions in which bradykinin is thought to play a significant role. Icatibant currently has orphan drug status in the United States and FDA approved on August 25, 2011.

Type
Small Molecule
Groups
Approved, Investigational
Structure
Thumb
Weight
Average: 1304.54
Monoisotopic: 1303.660795176
Chemical Formula
C59H89N19O13S
Synonyms
  • Icatibant
External IDs
  • HOE 140
  • HOE-140
  • HOE140
  • Hoechst 140
  • JE 049

Pharmacology

Indication

Approved for use in acute attacks of hereditary angioedema (HAE). Investigated for use/treatment in angioedema, liver disease, and burns and burn infections.

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

Icatibant is a potent, specific, competitive, and selective peptidomimetic bradykinin beta2-receptor antagonist (pA2 = 9.04). It has a modified peptide structure, and is the first bradykinin receptor antagonist to act on the guinea-pig trachea without demonstrating agonist effects. It also inhibits aminopeptidase N (Ki = 9.1 μM). If an IV dose of 0.4 and 0.8 mg/kg was infused over 4 hours, one may observe an inhibited response to bradykinin challenge for 6 - 8 hours following completion of infusion.

Mechanism of action

Bradykinin is a peptide-based hormone that is formed locally in tissues in response to a trauma and acts to increases vessel permeability, dilates blood vessels and causes smooth muscle cells to contract. Bradykinin plays an important role in the mediation of pain as surplus bradykinin is partly responsible for producing signs of inflammation by activating bradykinin B2 receptors. In patients with HAE, they have an absent or dysfunctional C1-esterase inhibitor. This inhibitor is responsible for the production of bradykinin in which displacement of bradykinin from B2 receptors by icatibant has an inhibitory effect on the receptor for a relatively long time.

TargetActionsOrganism
AB2 bradykinin receptor
antagonist
Humans
UAminopeptidase N
inhibitor
Humans
Absorption

The absolute bioavailability of icatibant following a 30 mg subcutaneous dose is approximately 97%. Maximum plasma concentrations (Cmax) of 974 ± 280 ng/mL was reached when a single subcutaneous dose of 30 mg was administered. The AUC was 2165 ± 568 ng∙hr/mL. Icatibant did not accumulate following multiple doses.

Volume of distribution

Vdss, subcutaneous injection = 29.0 ± 8.7 L.

Protein binding

Not Available

Metabolism

Icatibant is metabolized by proteolytic enzymes into inactive metabolites. The cytochrome P450 enzyme system is not involved with the metabolism of icatibant.

Route of elimination

Urine (<10% unchanged)

Half-life

After subcutaneous administration, mean elimination half-life was 1.4 ± 0.4 hours.

Clearance

Plasma clearance following subcutaneous administration was 245 ± 58 mL/min.

Adverse Effects
Adverseeffects
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Toxicity

Not Available

Pathways
Not Available
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
AbacavirAbacavir may decrease the excretion rate of Icatibant which could result in a higher serum level.
AceclofenacAceclofenac may decrease the excretion rate of Icatibant which could result in a higher serum level.
AcemetacinAcemetacin may decrease the excretion rate of Icatibant which could result in a higher serum level.
AcetaminophenAcetaminophen may decrease the excretion rate of Icatibant which could result in a higher serum level.
AcetazolamideAcetazolamide may increase the excretion rate of Icatibant which could result in a lower serum level and potentially a reduction in efficacy.
Acetylsalicylic acidThe risk or severity of angioedema can be increased when Acetylsalicylic acid is combined with Icatibant.
AclidiniumIcatibant may decrease the excretion rate of Aclidinium which could result in a higher serum level.
AcrivastineIcatibant may decrease the excretion rate of Acrivastine which could result in a higher serum level.
AcyclovirAcyclovir may decrease the excretion rate of Icatibant which could result in a higher serum level.
Adefovir dipivoxilAdefovir dipivoxil may decrease the excretion rate of Icatibant which could result in a higher serum level.
Interactions
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Food Interactions
No interactions found.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Icatibant acetate325O8467XK138614-30-9HKMZRZUEADSZDQ-DZJWSCHMSA-N
International/Other Brands
Firazyr
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
FirazyrInjection, solution30 mgSubcutaneousShire Pharmaceuticals Ireland Limited2020-12-16Not applicableEU flag
FirazyrInjection, solution30.0 mg/3mLSubcutaneousTakeda Pharmaceuticals America, Inc.2011-08-25Not applicableUS flag
FirazyrInjection, solution30 mgSubcutaneousShire Pharmaceuticals Ireland Limited2020-12-16Not applicableEU flag
FirazyrSolution10 mg / mLSubcutaneousTakeda2014-07-14Not applicableCanada flag
Icatibant AccordInjection, solution30 mgSubcutaneousAccord Healthcare S.L.U.2021-10-07Not applicableEU flag
Icatibant AccordInjection, solution30 mgSubcutaneousAccord Healthcare S.L.U.2021-10-07Not applicableEU flag
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
IcatibantInjection30 mg/3mLSubcutaneousCipla USA Inc.2020-07-13Not applicableUS flag
IcatibantInjection, solution30 mg/3mLSubcutaneousTakeda Pharmaceuticals America, Inc.2019-07-30Not applicableUS flag
IcatibantInjection, solution10 mg/1mLSubcutaneousFresenius Kabi USA, LLC2020-11-15Not applicableUS flag
IcatibantInjection, solution30 mg/3mLSubcutaneousLeucadia Pharmaceuticals2020-03-09Not applicableUS flag
IcatibantInjection, solution30.0 mg/3mLSubcutaneousGlenmark Pharmaceuticals Inc., USA2021-05-21Not applicableUS flag
IcatibantInjection30 mg/3mLSubcutaneousSlayback Pharma LLC2021-01-28Not applicableUS flag
IcatibantInjection, solution10 mg/1mLSubcutaneousTeva Pharmaceuticals USA, Inc.2019-07-15Not applicableUS flag
IcatibantInjection, solution30 mg/3mLSubcutaneousApotex Corp.2021-04-15Not applicableUS flag
SajazirInjection30 mg/3mLSubcutaneousCycle Pharmaceuticals Ltd-Uk2021-06-03Not applicableUS flag

Categories

ATC Codes
B06AC02 — Icatibant
Drug Categories
Classification
Not classified
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
7PG89G35Q7
CAS number
130308-48-4
InChI Key
QURWXBZNHXJZBE-SKXRKSCCSA-N
InChI
InChI=1S/C59H89N19O13S/c60-37(14-5-19-67-57(61)62)48(82)72-38(15-6-20-68-58(63)64)52(86)75-22-8-18-43(75)54(88)77-30-35(80)26-44(77)50(84)70-28-47(81)71-40(27-36-13-9-23-92-36)49(83)74-41(31-79)53(87)76-29-34-12-2-1-10-32(34)24-46(76)55(89)78-42-17-4-3-11-33(42)25-45(78)51(85)73-39(56(90)91)16-7-21-69-59(65)66/h1-2,9-10,12-13,23,33,35,37-46,79-80H,3-8,11,14-22,24-31,60H2,(H,70,84)(H,71,81)(H,72,82)(H,73,85)(H,74,83)(H,90,91)(H4,61,62,67)(H4,63,64,68)(H4,65,66,69)/t33-,35+,37+,38-,39-,40-,41-,42-,43-,44-,45-,46+/m0/s1
IUPAC Name
(2S)-2-{[(2S,3aS,7aS)-1-[(3R)-2-[(2S)-2-[(2S)-2-(2-{[(2S,4R)-1-[(2S)-1-[(2S)-2-[(2R)-2-amino-5-carbamimidamidopentanamido]-5-carbamimidamidopentanoyl]pyrrolidine-2-carbonyl]-4-hydroxypyrrolidin-2-yl]formamido}acetamido)-3-(thiophen-2-yl)propanamido]-3-hydroxypropanoyl]-1,2,3,4-tetrahydroisoquinoline-3-carbonyl]-octahydro-1H-indol-2-yl]formamido}-5-carbamimidamidopentanoic acid
SMILES
[H][C@]12C[C@]([H])(N(C(=O)[C@@]3([H])CC4=C(CN3C(=O)[C@H](CO)NC(=O)[C@H](CC3=CC=CS3)NC(=O)CNC(=O)[C@]3([H])C[C@@H](O)CN3C(=O)[C@@H]3CCCN3C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](N)CCCNC(N)=N)C=CC=C4)[C@@]1([H])CCCC2)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O

References

General References
  1. Cockcroft JR, Chowienczyk PJ, Brett SE, Bender N, Ritter JM: Inhibition of bradykinin-induced vasodilation in human forearm vasculature by icatibant, a potent B2-receptor antagonist. Br J Clin Pharmacol. 1994 Oct;38(4):317-21. [Article]
  2. Bork K, Frank J, Grundt B, Schlattmann P, Nussberger J, Kreuz W: Treatment of acute edema attacks in hereditary angioedema with a bradykinin receptor-2 antagonist (Icatibant). J Allergy Clin Immunol. 2007 Jun;119(6):1497-503. Epub 2007 Apr 5. [Article]
  3. FDA Approved Drug Products: FIRAZYR (icatibant) injection [Link]
Human Metabolome Database
HMDB0015624
KEGG Drug
D04492
PubChem Compound
71364
PubChem Substance
99443237
ChemSpider
5293384
BindingDB
50406750
RxNav
1148138
ChEBI
68556
ChEMBL
CHEMBL2028850
Therapeutic Targets Database
DCL000131
PharmGKB
PA164749185
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Icatibant
FDA label
Download (543 KB)
MSDS
Download (87.6 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedTreatmentHereditary Angioedema (HAE)1
4RecruitingBasic ScienceHeart Failure1
4TerminatedTreatmentACE Inhibitor-associated Angioedema1
3CompletedTreatmentACE Inhibitor-associated Angioedema1
3CompletedTreatmentAngioedema1
3CompletedTreatmentHereditary Angioedema (HAE)6
2CompletedPreventionHemodialysis-Induced Symptoms / Mitochondrial Diseases1
2CompletedTreatmentAngioedema1
2CompletedTreatmentCoronavirus Disease 2019 (COVID‑19)1
2CompletedTreatmentJoint Diseases1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, solutionSubcutaneous
Injection, solutionParenteral; Subcutaneous30 MG
Injection, solutionSubcutaneous30.0 mg/3mL
SolutionSubcutaneous10 mg / mL
SolutionSubcutaneous30 mg
InjectionSubcutaneous30 mg/3mL
Injection, solutionSubcutaneous10 mg/1mL
Injection, solutionSubcutaneous30 mg/3mL
Injection, solutionSubcutaneous30 MG
Injection, solution30 MG/3ML
Injection, solution30 MG
Injection, solutionParenteral
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US5648333No1997-07-152019-07-15US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubility1 mg/mL MSDS
Predicted Properties
PropertyValueSource
Water Solubility0.0362 mg/mLALOGPS
logP-2.2ALOGPS
logP-7.7ChemAxon
logS-4.6ALOGPS
pKa (Strongest Acidic)3.46ChemAxon
pKa (Strongest Basic)12.48ChemAxon
Physiological Charge3ChemAxon
Hydrogen Acceptor Count23ChemAxon
Hydrogen Donor Count18ChemAxon
Polar Surface Area516.22 Å2ChemAxon
Rotatable Bond Count30ChemAxon
Refractivity363.79 m3·mol-1ChemAxon
Polarizability135.1 Å3ChemAxon
Number of Rings7ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.5123
Blood Brain Barrier-0.8713
Caco-2 permeable-0.8198
P-glycoprotein substrateSubstrate0.8421
P-glycoprotein inhibitor INon-inhibitor0.8961
P-glycoprotein inhibitor IINon-inhibitor0.9801
Renal organic cation transporterNon-inhibitor0.6176
CYP450 2C9 substrateNon-substrate0.7753
CYP450 2D6 substrateNon-substrate0.7828
CYP450 3A4 substrateNon-substrate0.5958
CYP450 1A2 substrateNon-inhibitor0.661
CYP450 2C9 inhibitorNon-inhibitor0.8477
CYP450 2D6 inhibitorNon-inhibitor0.876
CYP450 2C19 inhibitorNon-inhibitor0.796
CYP450 3A4 inhibitorNon-inhibitor0.729
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9691
Ames testNon AMES toxic0.6483
CarcinogenicityNon-carcinogens0.8963
BiodegradationNot ready biodegradable0.898
Rat acute toxicity2.4262 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9506
hERG inhibition (predictor II)Inhibitor0.5187
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

Drugtargets2
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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
General Function
Type 1 angiotensin receptor binding
Specific Function
Receptor for bradykinin. It is associated with G proteins that activate a phosphatidylinositol-calcium second messenger system.
Gene Name
BDKRB2
Uniprot ID
P30411
Uniprot Name
B2 bradykinin receptor
Molecular Weight
44460.15 Da
References
  1. Privitera PJ, Beckstead RM, Yates P, Walgren R: Autoradiographic localization of [125I-Tyr0]bradykinin binding sites in brains of Wistar-Kyoto and spontaneously hypertensive rats. Cell Mol Neurobiol. 2003 Oct;23(4-5):805-15. [Article]
  2. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Zinc ion binding
Specific Function
Broad specificity aminopeptidase. Plays a role in the final digestion of peptides generated from hydrolysis of proteins by gastric and pancreatic proteases. May play a critical role in the pathogen...
Gene Name
ANPEP
Uniprot ID
P15144
Uniprot Name
Aminopeptidase N
Molecular Weight
109538.68 Da
References
  1. Bawolak MT, Fortin JP, Vogel LK, Adam A, Marceau F: The bradykinin B2 receptor antagonist icatibant (Hoe 140) blocks aminopeptidase N at micromolar concentrations: off-target alterations of signaling mediated by the bradykinin B1 and angiotensin receptors. Eur J Pharmacol. 2006 Dec 3;551(1-3):108-11. Epub 2006 Sep 8. [Article]

Drug created at March 19, 2008 16:16 / Updated at December 08, 2021 01:57