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Identification
- Summary
Ecallantide is a kallikrein inhibitor used to prevent and treat acute attacks caused by Hereditary Angioedema (HAE).
- Brand Names
- Kalbitor
- Generic Name
- Ecallantide
- DrugBank Accession Number
- DB05311
- Background
Ecallantide is a potent and selective human plasma kallikrein inhibitor that is indicated for the symptomatic treatment of hereditary angioedema. Ecallantide is a recombinant 60-amino-acid protein produced in Pichia pastoris yeast cells that contains three intramolecular disulfide bonds Label. It was discovered by phage display technology 4. It shares sequence similarities with the naturally occurring human protein tissue-factor pathway inhibitor (TFPI), which is also known lipoprotein-associated coagulation inhibitor (LACI) 5. The amino acid sequence of two compounds differ by seven amino acids 5.
Ecallantide works by blocking kallikrein to participate in the kallikrein-kinin system, which is a complex proteolytic cascade that initiates inflammatory and coagulation pathways Label. The protease plasma kallikerin facilitates the conversion of kininogen to bradykinin, which is a pro-inflammatory vasodilator that increases vascular permeability and induces pain 1. Hereditary angioedema is a rare autosomal dominant disorder with mutations to C1-esterase-inhibitor (C1-INH) located on Chromosome 11q, resulting in substantially lower levels of C4 and C1-INH activity Label. The disorder is associated with recurrent attacks of severe swelling and is thought to be caused by unregulated activity of kallikrein and excessive bradykinin production Label. By reversibly binding to plasma kallikrein, ecallantide displays a rapid on-rate and a slow off-rate that results in high affinity inhibition in the picomolar range 5. Ecallantide is marketed by FDA and EMA under the trade name Kalbitor for subcutaneous injection. Apart from its FDA and EMA indication, ecallantide has been used off label in the management of nonhistaminergic angioedema, not due to HAE 4.
- Type
- Biotech
- Groups
- Approved, Investigational
- Biologic Classification
- Protein Based Therapies
Other protein based therapies - Protein Chemical Formula
- C305H442N88O91S8
- Protein Average Weight
- 7054.0 Da (glycosylated)
- Sequences
> Ecallantide Sequence EAMHSFCAFKADDGPCRAAHPRWFFNIFTRQCEEFIYGGCEGNQNRFESLEECKKMCTRD
Download FASTA Format- Synonyms
- Ecallantide
- External IDs
- DX-88
Pharmacology
- Indication
Indicated for the symptomatic treatment of acute attacks of hereditary angioedema (HAE) in patients 12 years of age and older Label.
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Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Management of Acute attacks of hereditary angioedema •••••••••••• - Contraindications & Blackbox Warnings
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Intravenous administration of ecallantide doses ≥20 mg/m^2 resulted in prolongation of activated partial thromboplastin time (aPTT) without an indication of bleeding. Ecallantide administration has been associated with instances of arrhythmia. In a clinical trial of patients experiencing acute attacks of hereditary angioedema (HAE), intravenous administration of ecallantide demonstrated a significant improvement in symptoms affecting the oropharynx, abdomen, gastrointestinal tract, and limbs within 4 hours post-administration compared to placebo 3. A substantial decrease in the severity and duration of attacks was also observed in patients with moderate-to-severe HAE attacks 2. In clinical trials, ecallantide had no significant effect on the QTc interval, heart rate, or any other components of the ECG Label.
- Mechanism of action
The kallikrein-kinin system is a complex proteolytic cascade that promotes inflammatory and coagulation pathways. Human plasma kallikrein acts as a protease to mediate the conversion of High Molecular Weight (HMW) kininogen to bradykinin, which is a vasoactive mediator that increases vascular permeability and induces localized swelling, inflammation, and pain Label. The actions of kallikrein is regulated by the major endogenous inhibitor, C1-esterase-inhibitor (C1-INH). C1-INH also functions to regulate the activation of the complement and intrinsic coagulation (contact system pathway) Label, which also initiates the production of bradykinin. Upon audoactivation via exposure to negatively charged surfaces, factor XII promotes the generation of factor XIIa and kallikrein 2. C1-INH inhibits both factor XIIa and kallikrein 2. Kallikrein may in turn reciprocally activate more FXII 4. Hereditary angioedema is associated with a deficiency of the C1 inhibitor is caused by a mutation in the C1 INH gene 2. Resulting effect is excessive production of the vasodilator, bradykinin. The actions of bradykinin produce typical edematous signs and symptoms of hereditary angioedema by enhancing vascular and endothelial permeability, leading to increased outflow of plasma into the interstitium to produce local edema 2.
Ecallantide is a potent, specific and reversible plasma kallikrein inhibitor with an Inhibitory Constant (Ki) of 25 pM 2. Upon binding to kallikrein and blocking its active site, ecallantide prevents the conversion of HMW kininogen to bradykinin and attenuates the production of bradykinin Label. By blocking the actions of kallikrein, ecallantide also reduces further activation of fXIIa, halting the positive feedback mechanism leading to more kallikrein production 4.
Target Actions Organism APlasma kallikrein inhibitorHumans - Absorption
Following the administration of a single 30 mg subcutaneous dose of ecallantide in healthy subjects, a mean (± standard deviation) peak plasma concentration (Cmax) of 586 ± 106 ng/mL was achieved Label. The time to reach Cmax (Tmax) was approximately 2 to 3 hours post-dose Label. The mean area under the concentration-time curve (AUC) was 3017 ± 402 ng*hr/mL Label.
- Volume of distribution
The volume of distribution was 26.4 ± 7.8 L in healthy individuals Label. Intravenous and subcutaneous administration of ecallantide in patients and in healthy subjects resulted in rapid distribution in the vascular compartment 2.
- Protein binding
Not Available
- Metabolism
Ecallantide does not undergo metabolism mediated by the cytochrome P-450 system 4. No in vitro metabolism studies were performed with ecallantide Label.
- Route of elimination
Ecallantide undergoes renal elimination Label.
- Half-life
Following subcutaneous administration of 30 mg ecallantide, the mean elimination half-life was 2.0 ± 0.5 hours Label.
- Clearance
Plasma clearance was 153 ± 20 mL/min following a single subcutaneous dose of 30 mg ecallantide in healthy subjects Label. Inter-individual variability in patients and healthy individuals was 38% for clearance 2.
- Adverse Effects
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While there have been no reports of overdose with ecallantide, patients with hereditary angioedema have received single doses up to 90 mg intravenously without evidence of dose-related toxicity Label. There are no animal or human studies to assess the carcinogenic or mutagenic potential of ecallantide Label. In rats receiving subcutaneous doses up to 25 mg/kg/day, there were no observable effects on fertility reproductive performance Label.
An approximate lethal dose was identified as 25 mg/kg intravenously in rats and 5 mg/kg intravenously in rabbits 5.
- 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.Not Available
- Food Interactions
- No interactions found.
Products
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Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Kalbitor Injection, solution 10 mg/1mL Subcutaneous Takeda Pharma A/S 2010-02-02 Not applicable US 
Categories
- ATC Codes
- B06AC03 — Ecallantide
- Drug Categories
- Amino Acids, Peptides, and Proteins
- Analgesics
- Analgesics, Non-Narcotic
- Anti-Inflammatory Agents
- Antirheumatic Agents
- Blood and Blood Forming Organs
- Central Nervous System Agents
- Drugs Used in Hereditary Angioedema
- Kallikrein Inhibitors
- Kallikreins, antagonists & inhibitors
- Peripheral Nervous System Agents
- Plasma Kallikrein Inhibitor
- Sensory System Agents
- 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
- 5Q6TZN2HNM
- CAS number
- 460738-38-9
References
- General References
- Lehmann A: Ecallantide (DX-88), a plasma kallikrein inhibitor for the treatment of hereditary angioedema and the prevention of blood loss in on-pump cardiothoracic surgery. Expert Opin Biol Ther. 2008 Aug;8(8):1187-99. doi: 10.1517/14712598.8.8.1187 . [Article]
- Farkas H, Varga L: Ecallantide is a novel treatment for attacks of hereditary angioedema due to C1 inhibitor deficiency. Clin Cosmet Investig Dermatol. 2011;4:61-8. doi: 10.2147/CCID.S10322. Epub 2011 May 31. [Article]
- Schneider L, Lumry W, Vegh A, Williams AH, Schmalbach T: Critical role of kallikrein in hereditary angioedema pathogenesis: a clinical trial of ecallantide, a novel kallikrein inhibitor. J Allergy Clin Immunol. 2007 Aug;120(2):416-22. doi: 10.1016/j.jaci.2007.04.028. Epub 2007 Jun 7. [Article]
- Duffey H, Firszt R: Management of acute attacks of hereditary angioedema: role of ecallantide. J Blood Med. 2015 Apr 16;6:115-23. doi: 10.2147/JBM.S66825. eCollection 2015. [Article]
- Kalbitor, INN-ecallantide - European Medicines Agency - Europa EU [Link]
- FDA Approved Drug Products: KALBITOR (ecallantide) injection [Link]
- External Links
- PubChem Substance
- 347910073
- 658708
- ChEMBL
- CHEMBL1201837
- Wikipedia
- Ecallantide
- FDA label
- Download (294 KB)
Clinical Trials
- Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package Phase Status Purpose Conditions Count Start Date Why Stopped 100+ additional columns Unlock 175K+ rows when you subscribe.View sample dataNot Available Completed Not Available Hereditary Angioedema (HAE) 1 somestatus stop reason just information to hide 3 Completed Treatment Hereditary Angioedema (HAE) 3 somestatus stop reason just information to hide 2 Completed Prevention Bloodloss / Surgical Procedures, Operative 2 somestatus stop reason just information to hide 2 Completed Treatment Hereditary Angioedema (HAE) 1 somestatus stop reason just information to hide 2 Terminated Prevention Blood Loss During Surgery 1 somestatus stop reason just information to hide
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Injection, solution Subcutaneous 10 mg/1mL Solution Subcutaneous 10 mg - Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Solid
- Experimental Properties
- Not Available
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Participates in the surface-dependent activation of blood coagulation. Activates, in a reciprocal reaction, coagulation factor XII/F12 after binding to negatively charged surfaces. Releases bradykinin from HMW kininogen and may also play a role in the renin-angiotensin system by converting prorenin into renin
- Specific Function
- serine-type endopeptidase activity
- Gene Name
- KLKB1
- Uniprot ID
- P03952
- Uniprot Name
- Plasma kallikrein
- Molecular Weight
- 71342.175 Da
References
- Lehmann A: Ecallantide (DX-88), a plasma kallikrein inhibitor for the treatment of hereditary angioedema and the prevention of blood loss in on-pump cardiothoracic surgery. Expert Opin Biol Ther. 2008 Aug;8(8):1187-99. doi: 10.1517/14712598.8.8.1187 . [Article]
- Zhou Y, Zhang Y, Zhao D, Yu X, Shen X, Zhou Y, Wang S, Qiu Y, Chen Y, Zhu F: TTD: Therapeutic Target Database describing target druggability information. Nucleic Acids Res. 2024 Jan 5;52(D1):D1465-D1477. doi: 10.1093/nar/gkad751. [Article]
Drug created at November 18, 2007 18:23 / Updated at August 13, 2021 20:47