Kalbitor (ecallantide)

Ecallantide, a biosynthetic (recombinant DNA origin) protein based on the first Kunitz domain of human tissue factor pathway inhibitor, is a reversible and selective inhibitor of plasma kallikrein.

Ecallantide, a potent and selective inhibitor of plasma kallikrein, is a 60-amino acid protein produced by recombinant DNA technology through expression in yeast cells (Picha pastoris). Hereditary angioedema (HAE) is characterized by low plasma concentrations of functionally active C1-esterase inhibitor; this deficiency in C1-esterase inhibitor results in unrestrained activity of plasma kallikrein and an elevation in bradykinin levels, which leads to increased vascular permeability and angioedema. Ecallantide prevents binding of kallikrein to its target receptor, resulting in impaired cleavage of high molecular weight (HMW) kininogen, a cofactor formed during activation of the kallikrein-kinin (or contact) pathway.

Disruption of the catalytic conversion of HMW kininogen to the vasodilatory peptide bradykinin leads to a reduction in bradykinin-mediated HAE attack symptoms (e.g., swelling, inflammation, pain). Inhibition of kallikrein activity also inhibits the stimulation of complement C5a release, thereby interfering with the activation of a common step that regulates both the classical and alternative complement pathways.

Kallikrein also plays a role in regulating the intrinsic coagulation pathway through autocrine activation of factor XIIa; therefore, inhibition of kallikrein activity may result in a prolonged activated partial thromboplastin time (aPTT) and could potentially increase the risk of bleeding. Prolongation of thrombin time (i.e., exceeding 30 seconds) was reported in a few patients with HAE receiving ecallantide in clinical trials. However, no cases of abnormal patterns or increased risk of bleeding or thrombosis were reported in patients receiving the drug in clinical trials.

Transient prolongation of activated partial thromboplastin time (aPTT) has been observed in healthy individuals receiving ecallantide at dosages exceeding 20 mg/m2+ and by IV injection+; a transient prolongation of aPTT (i.e., a twofold increase compared with baseline) was observed in healthy individuals following administration of ecallantide 80 mg+ with resolution of the coagulopathy 4 hours after the dose. In the EDEMA-3 and EDEMA-4 studies, none of the patients with HAE attacks receiving ecallantide 30 mg by subcutaneous injection experienced a coagulopathy (i.e., aPTT exceeding 1.5 times the upper limit of normal). It has been suggested that hemostasis in patients receiving ecallantide is maintained by factors further along in the intrinsic coagulation pathway (e.g., factors X and XI), the extrinsic coagulation pathway, and platelets.

Some experts suggest that any effects on coagulation parameters resulting from subcutaneous administration of the drug would be expected to be transient due to the short half-life of the drug.

Cardiac toxicity has been reported in animals, including right-sided cardiac compromise (i.e., dilated atria and ventricles) in rats receiving ecallantide doses exceeding 20 mg/kg. No clinically important effects on QT interval (i.e., a corrected QT interval, Bazett's formula (QTc) exceeding 500 msec or a change in QTc exceeding 60 msec), heart rate, or ECG measurements were reported in patients receiving ecallantide during the EDEMA-4 trial.

In a pharmacokinetic study in healthy individuals, peak plasma concentrations of ecallantide were achieved at approximately 2-3 hours following a 30-mg dose of ecallantide administered by subcutaneous injection; an approximate bioavailability of 90% was reported with subcutaneous administration.

The mean half life of ecallantide is 2 hours. Ecallantide is eliminated in urine; however, since the drug is a small protein, metabolic catabolism (or degradation) is also a likely elimination process.

USES: This medication is used to treat an acute attack of a certain immune disease passed down through families (hereditary angioedema-HAE). Ecallantide blocks a natural substance produced by the body (kallikrein) which acts to increase amounts of another natural substance (bradykinin) thought to cause the symptoms seen during an acute attack of HAE. This medication does not cure HAE.

Ecallantide may lessen the symptoms during an acute attack of HAE such as rapid swelling and pain of the hands, feet, limbs, face, tongue, or throat. When attacks involve the intestines, symptoms may include abdominal pain/cramps, diarrhea or vomiting. Attacks of swelling may occur without reason.

However, anxiety, stress, sickness, and surgery may trigger attacks in some people.

Generic name: ecallantide
Pronunciation: (e-KAL-lan-tide)
Drug class: Plasma Kallikrein Inhibitors (Acute)
Therapeutic class: Cardiovascular Therapy Agents

The following indications are listed for Kalbitor:

• Hereditary Angioedema

Also known as: Hereditary Angioneurotic Edema.