Ecallantide, sold under the trade name Kalbitor, is a plasma kallikrein inhibitor, consisting of sixty amino acids. Kallikrein is a protease which is responsible for releasing bradykinin from its precursor kininogen. As an inflammatory mediator, the vasoactive peptide bradykinin can cause blood vessels to dilate and increase vascular permeability. Therefore, in patients with hereditary angioedema (HAE), high level of bradykinin due to C1-inhibitor deficiency causes fluid leakage from blood vessels, conducing swelling of tissues. Ecallantide provides an approach to lowering the level of bradykinin by inhibiting the activity of excessive plasma killikrein for the treatment of HAE.
Human plasma kallikrein is a protease associated with the conversion of precursor kininogen to vasoactive peptide bradykinin, which increases vascular permeability and leads to localized swelling, pain and inflammation. The kallikrein is regulated by C1-eaterase-inhibitor (C1-INH), the major endogenous inhibitor that modulates the activation of the complement and contact system pathway, which also activates the production of bradykinin. In patients with hereditary angioedema, the deficiency of C1-inhibitors permits the kallikrein to mediate excessive production of bradykinin. Ecallantide, as a potent and specific plasma kallikrein inhibitor, prevents the conversion of kininogen and the generation of bradykinin by binding to kallikrein and blocking the active site. Once the actions of kallikrein are limited, the further activation of fXIIa will be reduced and the positive feedback mechanism causing more kallikrein production will be interrupted.
Unlike another drug for the treatment of HAE named icatibant putting into effect as a bradykinin B2 receptors antagonist, ecallantide functions to inhibit the activity of human plasma kallikrein and stop the conversion of kininogen to bradykinin. In addition to be indicated for the treatment of acute attacks of HAE in patients aged above 12 years old, clinical trials about its prevention of blood loss in cardiothoracic surgery have been completed.
Pharmacokinetics and metabolism
After a single 30 mg subcutaneous administration of ecallantide in healthy subjects, the mean peak plasma concentration achieved 586±106 ng/mL in 2 to 3 hours and the area under the concentration-time curve is 3017±402 ng*hr/mL on average, while plasma clearance is 153±20 mL/min. The volume of distribution with ecallantide in healthy individuals is 26.4±7.8 L. Metabolism of ecallantide is not associated with the cytochrome P450 system and no metabolism studies with ecallantide are conducted in vitro. Ecallantide is excreted by renal elimination, while its mean elimination half-life is 2.0±0.5 hours after subcutaneous administration of 30 mg ecallantide. Toxicity tests in vitro demonstrate an approximate lethal dose is intravenously 25 mg/kg in rats and 5 mg/kg in rabbits.
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