Detailed description page of ThPDB2
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12146 details |
| Primary information | |
|---|---|
| ID | 12146 |
| Therapeutic ID | Th1290 |
| Protein Name | Ecallantide |
| Sequence | >Th1290_Ecallantide EAMHSFCAFKADDGPCRAAHPRWFFNIFTRQCEEFIYGGCEGNQNRFESLEECKKMCTRD |
| Molecular Weight | 7054 |
| Chemical Formula | C305H442N88O91S8 |
| Isoelectric Point | NA |
| Hydrophobicity | NA |
| Melting point | NA |
| Half-life | Following subcutaneous administration of 30 mg ecallantide, the mean elimination half-life was 2.0 ± 0.5 hours [FDA Label]. |
| 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 [FDA Label]. It was discovered by phage display technology [A32017]. It shares sequence similarities with the naturally occurring human protein tissue-factor pathway inhibitor (TFPI), which is also known lipoprotein-associated coagulation inhibitor (LACI) [L1458]. The amino acid sequence of two compounds differ by seven amino acids [L1458]. Ecallantide works by blocking kallikrein to participate in the kallikrein-kinin system, which is a complex proteolytic cascade that initiates inflammatory and coagulation pathways [FDA 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 [A3362]. 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 [FDA 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 [FDA 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 [L1458]. 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 [A32017]. |
| Indication/Disease | Indicated for the symptomatic treatment of acute attacks of hereditary angioedema (HAE) in patients 12 years of age and older [FDA Label]. |
| 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 [A32016]. A substantial decrease in the severity and duration of attacks was also observed in patients with moderate-to-severe HAE attacks [A32014]. In clinical trials, ecallantide had no significant effect on the QTc interval, heart rate, or any other components of the ECG [FDA 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 [FDA 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) [FDA 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 [A32014]. C1-INH inhibits both factor XIIa and kallikrein [A32014]. Kallikrein may in turn reciprocally activate more FXII [A32017]. Hereditary angioedema is associated with a deficiency of the C1 inhibitor is caused by a mutation in the C1 INH gene [A32014]. 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 [A32014]. Ecallantide is a potent, specific and reversible plasma kallikrein inhibitor with an Inhibitory Constant (Ki) of 25 pM [A32014]. Upon binding to kallikrein and blocking its active site, ecallantide prevents the conversion of HMW kininogen to bradykinin and attenuates the production of bradykinin [FDA Label]. By blocking the actions of kallikrein, ecallantide also reduces further activation of fXIIa, halting the positive feedback mechanism leading to more kallikrein production [A32017]. |
| 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 [FDA Label]. There are no animal or human studies to assess the carcinogenic or mutagenic potential of ecallantide [FDA Label]. In rats receiving subcutaneous doses up to 25 mg/kg/day, there were no observable effects on fertility reproductive performance [FDA Label]. An approximate lethal dose was identified as 25 mg/kg intravenously in rats and 5 mg/kg intravenously in rabbits [L1458]. |
| Metabolism | Ecallantide does not undergo metabolism mediated by the cytochrome P-450 system [A32017]. No _in vitro_ metabolism studies were performed with ecallantide [FDA Label]. |
| 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 [FDA Label]. The time to reach Cmax (Tmax) was approximately 2 to 3 hours post-dose [FDA Label]. The mean area under the concentration-time curve (AUC) was 3017 ± 402 ng*hr/mL [FDA Label]. |
| The volume of distribution was 26.4 ± 7.8 L in healthy individuals [FDA Label]. Intravenous and subcutaneous administration of ecallantide in patients and in healthy subjects resulted in rapid distribution in the vascular compartment [A32014]. | |
| Clearance | Plasma clearance was 153 ± 20 mL/min following a single subcutaneous dose of 30 mg ecallantide in healthy subjects [FDA Label]. Inter-individual variability in patients and healthy individuals was 38% for clearance [A32014]. |
| Categories | Peripheral Nervous System Agents |
| Patents Number | NA |
| Date of Issue | NA |
| Date of Expiry | NA |
| Drug Interaction | NA |
| Target | Plasma kallikrein |
| Brand Name | NA |
| Company | NA |
| Brand Description | NA |
| Prescribed For | NA |
| Chemical Name | NA |
| Formulation | NA |
| Physical Appearance | NA |
| Route of Administration | NA |
| Recommended Dosage | NA |
| Contraindication | (2S)-2-[[(2S)-2-[[(2S,3S)-2-[[(1R,2aS,4S,5aS,8aS,11aR,13S,14aS,16S,17aS,19S,20aS,22S,23aS,25S,26aS,28S,29aS,31R,32aS,35aS,36R,38aS,39S,41aS,42S,44aS,45S,48R,50aS,51S,53aS,54S,56aS,57S,59aS,60S,63S,66S,69S,72S,75S,78S,84S,87R,96S,99S)-22,42,45-tris(4-aminobutyl)-31-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-amino-4-carboxybutanoyl]amino]propanoyl]amino]-4-methylsulfanylbutanoyl]amino]-3-(1H-imidazol-5-yl)propanoyl]amino]-3-hydroxypropanoyl]amino]-3-phenylpropanoyl]amino]-29a,72,78-tris(2-amino-2-oxoethyl)-14a,75-bis(3-amino-3-oxopropyl)-2a,23a,25,32a,35a,66-hexabenzyl-26a,99-bis[(2S)-butan-2-yl]-17a,41a,59a,69-tetrakis(3-carbamimidamidopropyl)-5a,8a,51,54,63,84-hexakis(2-carboxyethyl)-13,16-bis(carboxymethyl)-20a-[(1S)-1-hydroxyethyl]-60-(hydroxymethyl)-96-[(4-hydroxyphenyl)methyl]-50a-(1H-imidazol-5-ylmethyl)-38a-(1H-indol-3-ylmethyl)-19,28,53a,56a-tetramethyl-57-(2-methylpropyl)-39-(2-methylsulfanylethyl)-1a,3,4a,7a,9,10a,12,13a,15,16a,18,19a,21,22a,24,25a,27,28a,30,31a,34a,37a,38,40a,41,43a,44,47,49a,50,52a,53,55a,56,58a,59,61a,62,65,68,71,74,77,80,83,86,89,92,95,98-pentacontaoxo-33,34,63a,64a,67a,68a-hexathia-a,2,3a,6a,8,9a,11,12a,14,15a,17,18a,20,21a,23,24a,26,27a,29,30a,33a,36a,37,39a,40,42a,43,46,48a,49,51a,52,54a,55,57a,58,60a,61,64,67,70,73,76,79,82,85,88,91,94,97-pentacontazapentacyclo[85.74.4.448,111.04,8.0144,148]nonahexacontahectane-36-carbonyl]amino]-3-hydroxybutanoyl]amino]-5-carbamimidamidopentanoyl]amino]butanedioic acid |
| Side Effects | NA |
| Useful Link 1 | Link |
| Useful Link 2 | NA |
| Remarks | NA |