Icatibant

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 is a synthetic decapeptide with 5 nonproteinogenic amino acid antagonist targeting the B2 receptors with a similar affinity to bradykinin. It is resistant to bradykinin-cleaving enzyme degradation and has a potency of 2-3 times higher than earlier B2 receptors antagonists, thus representing a new class of medication.1,4 It was investigated as a potential treatment of hereditary angioedema (HAE) as bradykinin was implicated in HAE swelling; specifically, mice lacking B2 receptors showed reduced swelling, thus demonstrating bradykinin involvement in the disease pathophysiology.1,5

Icatibant was approved by the FDA on August 25, 2011, and by the EMA in 2008 as a treatment for hereditary angioedema.8,9 The FDA approval was based on positive results obtained from 3 double-blind, randomized, controlled clinical trials known as FAST 1, 2, and 3, where a median time to almost complete symptom relief was observed to be 8 hours compared to 36 hours for the placebo treatment.8

Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Hormones / Peptides
Protein Chemical Formula
C59H89N19O13S
Protein Average Weight
1304.54 Da
Sequences
Not Available
Synonyms
  • Icatibant
External IDs
  • HOE 140
  • HOE-140
  • HOE140
  • Hoechst 140
  • JE 049

Pharmacology

Indication

Icatibant is indicated for the treatment of acute attacks of hereditary angioedema (HAE) in adults 18 years of age and older.7

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Treatment ofAcute attacks of hereditary angioedema••••••••••••••••••••••••••
Treatment ofAngioedema caused by ace inhibitors••• •••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

Following bradykinin challenge, intravenous administration of icatibant caused dose and time-dependent inhibition of the development of bradykinin-induced hypotension, vasodilation, and reflex tachycardia in healthy young subjects. Icatibant intravenous doses of 0.4 and 0.8 mg/kg infused over 4 hours inhibited response to bradykinin challenge for 6 to 8 hours following completion of the infusion. Based on exposure-response analysis, a subcutaneous dose of 30 mg icatibant is predicted to be effective against bradykinin challenge for at least 6 hours. The clinical significance of these findings is unknown.7

The effect of icatibant 30 and 90 mg following a single subcutaneous injection on QTc interval was evaluated in a randomized, placebo-, and active-controlled (moxifloxacin 400 mg) four-period crossover thorough QT study in 72 healthy subjects. In a study with demonstrated ability to detect small effects, the upper bound of the one-sided 95% confidence interval for the largest placebo-adjusted, baseline-corrected QTc based on individual correction method (QTcI) was below 10 ms, the threshold for regulatory concern. The dose of 90 mg is adequate to represent the high-exposure clinical scenario.7

Mechanism of action

Icatibant is a competitive antagonist selective for the bradykinin B2 receptor, with an affinity similar to bradykinin. Hereditary angioedema is caused by an absence or dysfunction of C1-esterase-inhibitor, a key regulator of the Factor XII/kallikrein proteolytic cascade that leads to bradykinin production. Bradykinin is a vasodilator thought to be responsible for the characteristic HAE symptoms of localized swelling, inflammation, and pain. Icatibant inhibits bradykinin from binding to the B2 receptor, thereby treating the clinical symptoms of an acute, episodic attack of HAE.7

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 were 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.7

The pharmacokinetics of icatibant have been characterized in studies using both intravenous and subcutaneous administration to healthy subjects and patients. The pharmacokinetic profile of icatibant in patients with HAE is similar to that in healthy subjects.7

The absolute bioavailability of icatibant following a 30 mg subcutaneous dose is approximately 97%. Following subcutaneous administration of a single 30 mg dose of icatibant to healthy subjects (N=96), a mean (± standard deviation) maximum plasma concentration (Cmax) of 974 ± 280 ng/mL was observed after approximately 0.75 hours. The mean area under the concentration-time curve (AUC0-∞) after a single 30 mg dose was 2165 ± 568 ng·hr/mL, with no evidence of accumulation of icatibant following three 30 mg doses administered 6 hours apart.7

Volume of distribution

Following subcutaneous administration, d volume of distribution at steady state (Vss) was 29.0 ± 8.7 L.7

Protein binding

No information is available on the protein binding of icatibant

Metabolism

Icatibant is metabolized by proteolytic enzymes into inactive metabolites. The cytochrome P450 enzyme system is not involved with the metabolism of icatibant.7

Route of elimination

Icatibant's inactive metabolites are primarily excreted in the urine, with less than 10% of the dose eliminated as unchanged drug.7

Half-life

Following subcutaneous administration, mean elimination half-life was 1.4 ± 0.4 hours.7

Clearance

Following subcutaneous administration, plasma clearance was 245 ± 58 mL/min.7

Adverse Effects
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Toxicity

Available data from published literature and the pharmacovigilance database with icatibant use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In animal reproduction studies, icatibant, administered by the subcutaneous route during the period of organogenesis, did not cause structural abnormalities in rats or rabbits; however, premature birth and abortion were observed in rabbits at doses approximately 0.025 times the maximum recommended human dose (MRHD) and higher. Decreased embryofetal survival was observed in rabbits at a subcutaneous dose that was 13 times the MRHD. In a pre- and post-natal development study in rats, delayed parturition was observed at subcutaneous doses 0.5 times the MRHD and higher, which resulted in deaths of dams at doses 2 times the MRHD and higher. Fetal death and early pup deaths were observed with doses 2 times the MRHD.7

Two-year studies were conducted in CD1 mice and Wistar rats to assess the carcinogenic potential of icatibant. No evidence of tumorigenicity was observed in mice and rats at icatibant subcutaneous doses up to 15 mg/kg/day (twice per week) and 6 mg/kg/day (daily), respectively (approximately 10-fold and 6-fold greater than the MRHD on an AUC basis, respectively).7

Icatibant tested negative for genotoxicity in the in vitro Ames bacterial reverse mutation test, in vitro Chinese hamster bone marrow chromosome aberration assay, and in vivo mouse micronucleus test.7

Daily subcutaneous administration of icatibant to rats and dogs caused ovarian, uterine, and testicular atrophy/degeneration and adverse effects on the mammary and prostate glands. In rats, testicular atrophy, reduced prostate gland secretion, decreased testosterone levels and degenerate corpora lutea occurred at doses greater than or equal to 3 mg/kg (approximately 5-fold greater than the MRHD in males and 2-fold greater than the MRHD in females on an AUC basis) and a decrease in developing ovarian follicles, mammary gland masculinization, and uterine atrophy occurred at doses greater than or equal to 10 mg/kg (approximately 6-fold greater than MRHD in females on an AUC basis). In dogs, reduced sperm counts and uterine atrophy occurred at doses greater than or equal to 1 mg/kg (approximately 2-fold greater than the MRHD on an AUC basis). Atrophy of the testes and prostate with decreased testosterone levels, decreased ovary size and decreased number of developing follicles occurred at a dose of 10 mg/kg (approximately 30-fold greater than the MRHD in males and 15-fold greater than at the MRHD in females on an AUC basis).7

In contrast to the effects of daily icatibant administration, toxicity to the ovary, uterus, testis, mammary gland, and prostate did not occur in dogs treated twice a week for 9 months. AUC exposures from a dose of 3 mg/kg in these dogs were 5- and 3-fold the MRHD exposures in men and women, respectively. Sperm counts and testosterone remained unaffected over the course of the study in male dogs dosed twice a week.7

Reproduction studies in male mice and rats with daily administration of icatibant found no effects on fertility or reproductive performance with intravenous doses up to 81 mg/kg (approximately 5-fold greater than the MRHD on a mg/m2 basis) or subcutaneous doses up to 10 mg/kg (approximately 11-fold greater than the MRHD on an AUC basis), respectively.7

In a clinical study evaluating a 90 mg dose (30 mg in each of 3 subcutaneous sites), the adverse event profile was similar to that seen with 30 mg administered in a single subcutaneous site.7

In another clinical study, a dose of 3.2 mg/kg administered intravenously (approximately 8 times the therapeutic dose for HAE) caused erythema, itching, and hypotension in healthy subjects. No therapeutic intervention was necessary.7

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.
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
FirazyrSolution10 mg / mLSubcutaneousTakeda2014-07-14Not applicableCanada flag
FirazyrInjection, solution30 mgSubcutaneousTakeda Pharmaceuticals International Ag2020-12-16Not applicableEU flag
FirazyrInjection, solution30.0 mg/3mLSubcutaneousTakeda Pharmaceuticals America, Inc.2011-08-25Not applicableUS flag
FirazyrInjection, solution30 mgSubcutaneousTakeda Pharmaceuticals International Ag2020-12-16Not applicableEU flag
Icatibant AccordInjection, solution30 mgSubcutaneousAccord Healthcare S.L.U.2021-10-07Not applicableEU flag
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
IcatibantInjection, solution30.0 mg/3mLSubcutaneousGlenmark Pharmaceuticals Inc., USA2021-05-21Not applicableUS flag
IcatibantInjection, solution10 mg/1mLSubcutaneousTeva Pharmaceuticals USA, Inc.2019-07-15Not applicableUS flag
IcatibantInjection30 mg/3mLSubcutaneousSlayback Pharma LLC2021-01-28Not applicableUS flag
IcatibantInjection, solution30 mg/3mLSubcutaneousbryant ranch prepack2021-04-15Not applicableUS flag
IcatibantInjection, solution30 mg/3mLSubcutaneousApotex Corp.2021-04-15Not applicableUS flag

Categories

ATC Codes
B06AC02 — Icatibant
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
7PG89G35Q7
CAS number
130308-48-4

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. Bas M, Greve J, Stelter K, Havel M, Strassen U, Rotter N, Veit J, Schossow B, Hapfelmeier A, Kehl V, Kojda G, Hoffmann TK: A randomized trial of icatibant in ACE-inhibitor-induced angioedema. N Engl J Med. 2015 Jan 29;372(5):418-25. doi: 10.1056/NEJMoa1312524. [Article]
  4. Floccard B, Hautin E, Bouillet L, Coppere B, Allaouchiche B: An evidence-based review of the potential role of icatibant in the treatment of acute attacks in hereditary angioedema type I and II. Core Evid. 2012;7:105-14. doi: 10.2147/CE.S24743. Epub 2012 Sep 27. [Article]
  5. Campos RA, Valle SO, Franca AT, Cordeiro E, Serpa FS, Mello YF, Malheiros T, Toledo E, Mansour E, Fusaro G, Grumach AS: Icatibant, an inhibitor of bradykinin receptor 2, for hereditary angioedema attacks: prospective experimental single-cohort study. Sao Paulo Med J. 2014;132(5):261-5. doi: 10.1590/1516-3180.2014.1325652. Epub 2014 Jul 22. [Article]
  6. FDA Approved Drug Products: FIRAZYR (icatibant) injection [Link]
  7. FDA Approved Drug Products:FIRAZYR (icatibant) Injection, for subcutaneous use (Jan 2024) [Link]
  8. FDA Approves Shire's FIRAZYR® (icatibant injection) for Acute Attacks of Hereditary Angioedema (HAE) [Link]
  9. Shire Receives European Approval for Label Extension of FIRAZYR® (icatibant injection) for the Symptomatic Treatment of Acute HAE Attacks in Paediatric Patients [Link]
Human Metabolome Database
HMDB0015624
KEGG Drug
D04492
PubChem Compound
71364
PubChem Substance
99443237
ChemSpider
5293384
BindingDB
50403371
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

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
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
SolutionSubcutaneous30 mg / 3 mL
Injection, solutionParenteral30 mg
Injection, solutionParenteral30 mg/3ml
Injection, solution30 MG
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

Targets

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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]
  3. FDA Approved Drug Products:FIRAZYR (icatibant) Injection, for subcutaneous use (Jan 2024) [Link]
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 March 18, 2024 16:48