Chemical formula: C₃₀₅H₄₄₂N₈₈O₉₁S₈
Hereditary angioedema (HAE) is a rare genetic disorder caused by mutations to C1-esterase-inhibitor (C1-INH) located on Chromosome 11q and inherited as an autosomal dominant trait. HAE is characterized by low levels of C1-INH activity and low levels of C4. C1-INH functions to regulate the activation of the complement and intrinsic coagulation (contact system pathway) and is a major endogenous inhibitor of plasma kallikrein. The kallikrein-kinin system is a complex proteolytic cascade involved in the initiation of both inflammatory and coagulation pathways. One critical aspect of this pathway is the conversion of High Molecular Weight (HMW) kininogen to bradykinin by the protease plasma kallikrein. In HAE, normal regulation of plasma kallikrein activity and the classical complement cascade is therefore not present. During attacks, unregulated activity of plasma kallikrein results in excessive bradykinin generation. Bradykinin is a vasodilator which is thought by some to be responsible for the characteristic HAE symptoms of localized swelling, inflammation, and pain.
Ecallantide is a potent (Ki=25 pM), selective, reversible inhibitor of plasma kallikrein. Ecallantide binds to plasma kallikrein and blocks its binding site, inhibiting the conversion of HMW kininogen to bradykinin. By directly inhibiting plasma kallikrein, ecallantide reduces the conversion of HMW kininogen to bradykinin and thereby treats symptoms of the disease during acute episodic attacks of HAE.
No exposure-response relationships for ecallantide to components of the complement or kallikrein-kinin pathways have been established.
The effect of ecallantide on activated partial thromboplastin time (aPTT) was measured because of potential effect on the intrinsic coagulation pathway. Prolongation of aPTT has been observed following intravenous dosing of ecallantide at doses ≥20 mg/m2. At 80 mg administered intravenously in healthy subjects, aPTT values were prolonged approximately two-fold over baseline values and returned to normal by 4 hours post-dose.
For patients taking ecallantide, no significant QT prolongation has been seen. In a randomized, placebo-controlled trial (EDEMA4) studying the 30 mg subcutaneous dose versus placebo, 12-lead ECGs were obtained at baseline, 2 hours and 4 hours post-dose (covering the time of expected Cmax), and at follow-up (day 7). ECGs were evaluated for PR interval, QRS complex, and QTc interval. Ecallantide had no significant effect on the QTc interval, heart rate, or any other components of the ECG.
Following the administration of a single 30 mg subcutaneous dose of ecallantide to healthy subjects, a mean (± standard deviation) maximum plasma concentration of 586 ± 106 ng/mL was observed approximately 2 to 3 hours post-dose. The mean area under the concentration-time curve was 3017 ± 402 ng*hr/mL. Following administration, plasma concentration declined with a mean elimination half-life of 2.0 ± 0.5 hours. Plasma clearance was 153 ± 20 mL/min and the volume of distribution was 26.4 ± 7.8 L. Based on a population pharmacokinetic analysis, body weight, age, and gender were not found to affect ecallantide exposure significantly. Ecallantide is a small protein (7054 Da) and renal elimination in the urine of treated subjects has been demonstrated.
No pharmacokinetic data are available in patients or subjects with hepatic or renal impairment.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.