Recombinant C1 Esterase Inhibitor: Treatment for Hereditary Angioedema

1. C1 Esterase Inhibitor (Recombinant) • DrugbankID : DB09228 • Molecular Weight (Daltons):67000 • Half life :2.4-2.7 hr • Description: • C1 Esterase Inhibitor (Recombinant) is a recombinant analogue of endogenous complement component-1 esterase inhibitor (rhC1INH), purified from the milk of transgenic rabbits. The primary function of endogenous C1INH is to regulate the activation of the complement and contact system pathways. It does this through inhibition of several target proteases within these pathways including activated C1s, kallikrein, factor XIIa and factor XIa. C1 esterase inhibitor has also been shown to inhibit the action of thrombin within the coagulation pathway, and tPA and plasmin within the fibrinolytic pathway. Deficiency of C1-inhibitor permits plasma kallikrein activation, which leads to the production of the vasoactive peptide bradykinin. Additionally, C4 and C2 cleavage goes unchecked, resulting in auto-activation of the complement system. Down-stream effects of the lack of enzyme inhibition by C1 esterase inhibitor results in swelling due to leakage of fluid from blood vessels into connective tissue and consequently the presentation of hereditary angioedema (HAE). Marketed as the product Ruconest (FDA), this drug is indicated for the treatment of acute attacks of hereditary angioedema (HAE) due to C1 esterase inhibitor deficiency in adults. Intravenous replacement of C1 esterase inhibitor results in reversal of acute symptoms of HAE.

2. Indication : For the treatment of acute attacks of hereditary angioedema (HAE) due to C1 esterase inhibitor deficiency in adults. Pharmacodynamics : A dose of 50 U/kg of Ruconest increases plasma C1INH activity levels to greater than 0.7 U/mL (the lower limit of normal) in HAE patients.

3. Mechanism of action : The primary function of endogenous C1INH is to regulate the activation of the complement and contact system pathways. It does this through inhibition of several target proteases within these pathways including activated C1s, kallikrein, factor XIIa and factor XIa. C1 esterase inhibitor has also been shown to inhibit the action of thrombin within the coagulation pathway, and tPA and plasmin within the fibrinolytic pathway. Deficiency of C1-inhibitor permits plasma kallikrein activation, which leads to the production of the vasoactive peptide bradykinin. Additionally, C4 and C2 cleavage goes unchecked, resulting in auto-activation of the complement system. Down-stream effects of the lack of enzyme inhibition by C1 esterase inhibitor results in swelling due to leakage of fluid from blood vessels into connective tissue and consequently the presentation of hereditary angioedema (HAE). Replacement of C1 esterase inhibitor results in a reversal of these effects. Absorption : Mean Cmax was found to be 1.2 U/mL and Tmax was 0.31 ± 0.10 hr following administration of 50 U/kg. Clearance : Clearance was found to be 1207 ± 414 mL/hr following administration of 50 U/kg.

4. Categories: Blood and Blood Forming Organs • Targets :Complement C1r subcomponent, Complement C1s subcomponent, Plasma kallikrein, Coagulation factor XII, Prothrombin, Coagulation factor XI, Tissue-type plasminogen activator • Brands : Ruconest • Company : Tjoapack Netherlands Bv • Form : Powder and liquid for solution • Route of administration : Intravenous

5. Dosage :<84 kg: 50 IU/kg infused over 5 minutes; not to exceed 4200 IU/dose Contraindication : History of life-threatening immediate hypersensitivity reactions to C1 esterase inhibitor preparations, including anaphylaxis Side effects : Severe hypersensitivity reactions may occur during or after injection; signs and symptoms include hives, generalized urticaria, tightness of the chest, wheezing, hypotension, and/or anaphylaxis

6. Useful links https://www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsBLAs/FractionatedPlasmaProducts/UCM405634.pdf , http://reference.medscape.com/drug/ruconest-c1-esterase-inhibitor-recombinant-999953#5