Identification

Name
Ecallantide
Accession Number
DB05311
Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Other protein based therapies
Description

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].

Protein chemical formula
C305H442N88O91S8
Protein average weight
7054.0 Da (glycosylated)
Sequences
> Ecallantide Sequence
EAMHSFCAFKADDGPCRAAHPRWFFNIFTRQCEEFIYGGCEGNQNRFESLEECKKMCTRD
Download FASTA Format
Synonyms
Not Available
External IDs
DX-88
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
KalbitorInjection, solution10 mg/1mLSubcutaneousDyax Corp.2010-02-02Not applicableUs
Categories
UNII
5Q6TZN2HNM
CAS number
460738-38-9

Pharmacology

Indication

Indicated for the symptomatic treatment of acute attacks of hereditary angioedema (HAE) in patients 12 years of age and older [Label].

Associated Conditions
Pharmacodynamics

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].

TargetActionsOrganism
APlasma kallikrein
inhibitor
Human
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].

Toxicity

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].

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
Not Available
Food Interactions
Not Available

References

General References
  1. 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 . [PubMed:18613770]
  2. 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. [PubMed:21760740]
  3. 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. [PubMed:17559913]
  4. 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. [PubMed:25931832]
  5. Kalbitor, INN-ecallantide - European Medicines Agency - Europa EU [Link]
External Links
PubChem Substance
347910073
ChEMBL
CHEMBL1201837
Wikipedia
Ecallantide
ATC Codes
B06AC03 — Ecallantide
FDA label
Download (294 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1TerminatedTreatmentCentral Retinal Vein Occlusion (CRVO) / Macular Edema (ME)1
2CompletedPreventionBloodloss / Surgical Procedures, Operative2
2CompletedTreatmentHereditary Angioedema (HAE)1
2RecruitingTreatmentHereditary Angioedema Types I and II1
2TerminatedPreventionBlood Loss,Surgical1
2TerminatedTreatmentACE Inhibitor Induced Angioedema1
2, 3WithdrawnTreatmentHereditary Angioedema / Hereditary Angioedema (HAE)1
3CompletedTreatmentHereditary Angioedema (HAE)1
3CompletedTreatmentHereditary Angioedema / Hereditary Angioedema (HAE)2
Not AvailableCompletedNot AvailableHereditary Angioedema / Hereditary Angioedema (HAE)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Injection, solutionSubcutaneous10 mg/1mL
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available

Taxonomy

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

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Serine-type endopeptidase activity
Specific Function
The enzyme cleaves Lys-Arg and Arg-Ser bonds. It activates, in a reciprocal reaction, factor XII after its binding to a negatively charged surface. It also releases bradykinin from HMW kininogen an...
Gene Name
KLKB1
Uniprot ID
P03952
Uniprot Name
Plasma kallikrein
Molecular Weight
71369.205 Da
References
  1. 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 . [PubMed:18613770]

Drug created on November 18, 2007 11:23 / Updated on November 02, 2018 06:09