Ecallantide

Ecallantide
Mass / length primary structure	7.1 kDa
Identifier
External IDs	CAS number : 460738-38-9;
Drug information
ATC code	B02 AB
Drug class	Kunitz domain peptides

Ecallantide (DX-88) is a drug that is used to treat hereditary angioedema . This to the group of Kunitz domain peptides belonging biopharmaceutical is an inhibitor ( inhibitor ) of the enzyme kallikrein . Ecallantide was approved by the US FDA in 2009 and has since been marketed in the US by the pharmaceutical company Dyax under the brand name Kalbitor ™. Approval for the European market is currently pending.

Clinical information

Application areas (indications)

Ecallantide is approved for the US market for the treatment of patients over the age of 16 with hereditary angioedema. This is a rare inherited disease that is characterized by severe and often painful swelling in the abdomen ( abdomen may occur), the face, the hands and the respiratory tract.

Contraindications (contraindications)

Ecallantide must not be used in patients with a known hypersensitivity to this active substance. In clinical trials , up to 4% of patients reacted with signs of an anaphylactic reaction .

Interactions

No information is available on possible interactions between ecallantide and other medicinal products. These have not yet been investigated clinically or experimentally.

Adverse drug effects

In clinical safety studies on 255 patients, headache , nausea , fatigue and diarrhea were frequently observed as adverse drug reactions. Respiratory infections, fever , vomiting , itching, and upper abdominal pain also occurred with a frequency of more than 5% . Safety-limiting hypersensitivity reactions, which are attributed to the body's own immune response to ecallantide, could be observed in up to 4% of the patients.

pharmacology

Pharmacodynamics (mode of action)

Hereditary angioedema is a rare, genetic disease. It is caused by a mutation in the gene that codes for the C1 esterase inhibitor . This endogenous inhibitor regulates various physiological signal transduction pathways , including the kallikrein - kinin pathway. At a key point of this pathway is from kininogen the inflammatory mediator bradykinin split off. A dysfunction of the C1 esterase inhibitor in the context of hereditary angioedema thus leads to characteristic swellings in the abdomen, face, hands and airways. Attacks, which usually last 1 to 5 days, are often painful and can be life-threatening if angioedema occurs in the larynx .

As a selective and reversible inhibitor of the enzyme kallikrein, ecallantide inhibits the production of bradykinin, which is responsible for swelling. Ecallantide intervenes in the kallikrein-kinin pathway at a later point in time than the C1 esterase inhibitor.

Pharmacokinetics

After subcutaneous administration of ecallantide, its maximum plasma concentration is reached after 2 to 3 hours. The plasma half-life is two hours. As a peptide with a molar mass of about 7 kDa , elimination occurs primarily via the kidneys and urine .

biochemistry

Ecallantide is a genetically engineered peptide consisting of 60 amino acids . Using the phage display , it was selected from a library of Kunitz domains derived from those of the tissue factor pathway inhibitor . The yeast Pichia pastoris serves as the production organism .

literature

Zuraw B, Yasothan U, Kirkpatrick P: Ecallantide . In: Nat Rev Drug Discov . 9, No. 3, March 2010, pp. 189-90. doi : 10.1038 / nrd3125 . PMID 20190785 .

Web links

Dyax Corp .: Full prescibing information Kalbitor (PDF; 169 kB) 2009. Retrieved on May 2, 2010.

Individual evidence

↑ ^a ^b ^c ^d ^e Dyax Corp .: Full prescibing information Kalbitor (PDF; 169 kB) 2009. Retrieved on May 2, 2010.
↑ 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 . In: J. Allergy Clin. Immunol. . 120, No. 2, August 2007, pp. 416-22. doi : 10.1016 / j.jaci.2007.04.028 . PMID 17559913 .
^ Davis AE, Mejia P, Lu F: Biological activities of C1 inhibitor . In: Mol. Immunol. . 45, No. 16, October 2008, pp. 4057-63. doi : 10.1016 / j.molimm.2008.06.028 . PMID 18674818 . PMC 2626406 (free full text).
^ Ley AC, Markland W, Ladner RC: Obtaining a family of high-affinity, high-specificity protein inhibitors of plasmin and plasma kallikrein . In: Mol Divers . . 2, No. 1-2, October 1996, pp. 119-24. PMID 9238642 .
↑ Markland W, Ley AC, Ladner RC: Iterative optimization of high-affinity protease inhibitors using phage display. 2. Plasma kallikrein and thrombin . In: Biochemistry . 35, No. 24, June 1996, pp. 8058-67. doi : 10.1021 / bi952629y . PMID 8672510 .

[Dyax-1] Dyax Corp .: Full prescibing information Kalbitor (PDF; 169 kB) 2009. Retrieved on May 2, 2010.

[pmid17559913-2] 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 . In: J. Allergy Clin. Immunol. . 120, No. 2, August 2007, pp. 416-22. doi : 10.1016 / j.jaci.2007.04.028 . PMID 17559913 .

[pmid18674818-3] Davis AE, Mejia P, Lu F: Biological activities of C1 inhibitor . In: Mol. Immunol. . 45, No. 16, October 2008, pp. 4057-63. doi : 10.1016 / j.molimm.2008.06.028 . PMID 18674818 . PMC 2626406 (free full text).

[pmid9238642-4] Ley AC, Markland W, Ladner RC: Obtaining a family of high-affinity, high-specificity protein inhibitors of plasmin and plasma kallikrein . In: Mol Divers . . 2, No. 1-2, October 1996, pp. 119-24. PMID 9238642 .

[pmid8672510-5] Markland W, Ley AC, Ladner RC: Iterative optimization of high-affinity protease inhibitors using phage display. 2. Plasma kallikrein and thrombin . In: Biochemistry . 35, No. 24, June 1996, pp. 8058-67. doi : 10.1021 / bi952629y . PMID 8672510 .