Identification
NameConestat alfa
Accession NumberDB09228
TypeBiotech
GroupsApproved
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.

Protein structureDb09228
Related Articles
Protein chemical formulaNot Available
Protein average weight67000.0 Da
SequencesNot Available
Synonyms
C1 Esterase Inhibitor (Recombinant)
C1 Inhibitor (Recombinant)
Complement C1 esterase inhibitor
Human C1-inhibitor (recombinant, rabbit derived)
Recombinant complement C1 esterase inhibitor
Recombinant human C1 inhibitor
Recombinant human C1-inhibitor
Recombinant human C1-inhibitor rabbit milk derived
External IDs Not Available
Product Ingredients Not Available
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
RuconestInjection, powder, for solution2100 U/1IntravenousSantarus, Inc..2014-09-22Not applicableUs
RuconestInjection, powder, for solution2100 U/1IntravenousTjoapack Netherlands Bv2016-09-19Not applicableUs
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International Brands
NameCompany
RuconestPharming
Brand mixturesNot Available
Categories
UNII5QS67N4551
CAS number80295-38-1
Pharmacology
Indication

For the treatment of acute attacks of hereditary angioedema (HAE) due to C1 esterase inhibitor deficiency in adults.

Structured Indications
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.

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.

TargetKindPharmacological actionActionsOrganismUniProt ID
Complement C1r subcomponentProteinyes
inhibitor
HumanP00736 details
Complement C1s subcomponentProteinyes
inhibitor
HumanP09871 details
Plasma kallikreinProteinyes
inhibitor
HumanP03952 details
Coagulation factor XIIProteinyes
inhibitor
HumanP00748 details
ProthrombinProteinyes
inhibitor
HumanP00734 details
Coagulation factor XIProteinyes
inhibitor
HumanP03951 details
Tissue-type plasminogen activatorProteinyes
inhibitor
HumanP00750 details
Related Articles
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.

Volume of distributionNot Available
Protein bindingNot Available
MetabolismNot Available
Route of elimination

Elimination half-life was approximately 2.5 hours.

Half lifeNot Available
Clearance

Clearance was found to be 1207 ± 414 mL/hr following administration of 50 U/kg.

Toxicity

The common adverse reactions (≥ 2%) reported in clinical trials were headache, nausea, and diarrhea.

Serious arterial and venous thromboembolic (TE) events have been reported at the recommended dose of plasma derived C1 esterase inhibitor products in patients with risk factors. Risk factors may include the presence of an indwelling venous catheter/access device, prior history of thrombosis, underlying atherosclerosis, use of oral contraceptives or certain androgens, morbid obesity, and immobility. Monitor patients with known risk factors for TE events during and after administration.

Affected organismsNot Available
PathwaysNot Available
Pharmacogenomic Effects/ADRs Not Available
Interactions
Drug Interactions
DrugInteractionDrug group
AllylestrenolAllylestrenol may increase the thrombogenic activities of C1 Esterase Inhibitor (Recombinant).Approved
AltrenogestAltrenogest may increase the thrombogenic activities of C1 Esterase Inhibitor (Recombinant).Vet Approved
BazedoxifeneBazedoxifene may increase the thrombogenic activities of C1 Esterase Inhibitor (Recombinant).Approved, Investigational
ChlorotrianiseneChlorotrianisene may increase the thrombogenic activities of C1 Esterase Inhibitor (Recombinant).Withdrawn
Conjugated estrogensConjugated Equine Estrogens may increase the thrombogenic activities of C1 Esterase Inhibitor (Recombinant).Approved
DesogestrelDesogestrel may increase the thrombogenic activities of C1 Esterase Inhibitor (Recombinant).Approved
DienestrolDienestrol may increase the thrombogenic activities of C1 Esterase Inhibitor (Recombinant).Approved
DienogestDienogest may increase the thrombogenic activities of C1 Esterase Inhibitor (Recombinant).Approved
DiethylstilbestrolDiethylstilbestrol may increase the thrombogenic activities of C1 Esterase Inhibitor (Recombinant).Approved
DihydrotestosteroneDihydrotestosterone may increase the thrombogenic activities of C1 Esterase Inhibitor (Recombinant).Illicit
DrospirenoneDrospirenone may increase the thrombogenic activities of C1 Esterase Inhibitor (Recombinant).Approved
DydrogesteroneDydrogesterone may increase the thrombogenic activities of C1 Esterase Inhibitor (Recombinant).Approved, Withdrawn
EquolS Equol may increase the thrombogenic activities of C1 Esterase Inhibitor (Recombinant).Investigational
EstradiolEstradiol may increase the thrombogenic activities of C1 Esterase Inhibitor (Recombinant).Approved, Investigational, Vet Approved
EstriolEstriol may increase the thrombogenic activities of C1 Esterase Inhibitor (Recombinant).Approved, Vet Approved
EstroneEstrone may increase the thrombogenic activities of C1 Esterase Inhibitor (Recombinant).Approved
Ethinyl EstradiolEthinyl Estradiol may increase the thrombogenic activities of C1 Esterase Inhibitor (Recombinant).Approved
Ethynodiol diacetateEthynodiol diacetate may increase the thrombogenic activities of C1 Esterase Inhibitor (Recombinant).Approved
EtonogestrelEtonogestrel may increase the thrombogenic activities of C1 Esterase Inhibitor (Recombinant).Approved, Investigational
FluoxymesteroneFluoxymesterone may increase the thrombogenic activities of C1 Esterase Inhibitor (Recombinant).Approved, Illicit
GenisteinGenistein may increase the thrombogenic activities of C1 Esterase Inhibitor (Recombinant).Investigational
GestodeneGestodene may increase the thrombogenic activities of C1 Esterase Inhibitor (Recombinant).Approved
GestrinoneGestrinone may increase the thrombogenic activities of C1 Esterase Inhibitor (Recombinant).Approved
HexestrolHexestrol may increase the thrombogenic activities of C1 Esterase Inhibitor (Recombinant).Withdrawn
Hydroxyprogesterone caproateHydroxyprogesterone caproate may increase the thrombogenic activities of C1 Esterase Inhibitor (Recombinant).Approved
LevonorgestrelLevonorgestrel may increase the thrombogenic activities of C1 Esterase Inhibitor (Recombinant).Approved, Investigational
LynestrenolLynestrenol may increase the thrombogenic activities of C1 Esterase Inhibitor (Recombinant).Investigational
MedrogestoneMedrogestone may increase the thrombogenic activities of C1 Esterase Inhibitor (Recombinant).Approved
Medroxyprogesterone acetateMedroxyprogesterone acetate may increase the thrombogenic activities of C1 Esterase Inhibitor (Recombinant).Approved, Investigational
Megestrol acetateMegestrol acetate may increase the thrombogenic activities of C1 Esterase Inhibitor (Recombinant).Approved, Vet Approved
MestranolMestranol may increase the thrombogenic activities of C1 Esterase Inhibitor (Recombinant).Approved
MethallenestrilMethallenestril may increase the thrombogenic activities of C1 Esterase Inhibitor (Recombinant).Experimental
MethyltestosteroneMethyltestosterone may increase the thrombogenic activities of C1 Esterase Inhibitor (Recombinant).Approved
NomegestrolNomegestrol may increase the thrombogenic activities of C1 Esterase Inhibitor (Recombinant).Approved
NorethisteroneNorethisterone may increase the thrombogenic activities of C1 Esterase Inhibitor (Recombinant).Approved
OxandroloneOxandrolone may increase the thrombogenic activities of C1 Esterase Inhibitor (Recombinant).Approved, Investigational
OxymetholoneOxymetholone may increase the thrombogenic activities of C1 Esterase Inhibitor (Recombinant).Approved, Illicit
Polyestradiol phosphatePolyestradiol phosphate may increase the thrombogenic activities of C1 Esterase Inhibitor (Recombinant).Approved
ProgesteroneProgesterone may increase the thrombogenic activities of C1 Esterase Inhibitor (Recombinant).Approved, Vet Approved
PromestrienePromestriene may increase the thrombogenic activities of C1 Esterase Inhibitor (Recombinant).Investigational
QuinestrolQuinestrol may increase the thrombogenic activities of C1 Esterase Inhibitor (Recombinant).Approved
SecoisolariciresinolSecoisolariciresinol may increase the thrombogenic activities of C1 Esterase Inhibitor (Recombinant).Investigational
StanozololStanozolol may increase the thrombogenic activities of C1 Esterase Inhibitor (Recombinant).Approved, Vet Approved
Synthetic Conjugated Estrogens, ASynthetic Conjugated Estrogens, A may increase the thrombogenic activities of C1 Esterase Inhibitor (Recombinant).Approved
Synthetic Conjugated Estrogens, BSynthetic Conjugated Estrogens, B may increase the thrombogenic activities of C1 Esterase Inhibitor (Recombinant).Approved
TestosteroneTestosterone may increase the thrombogenic activities of C1 Esterase Inhibitor (Recombinant).Approved, Investigational
TiboloneTibolone may increase the thrombogenic activities of C1 Esterase Inhibitor (Recombinant).Approved
ZeranolZeranol may increase the thrombogenic activities of C1 Esterase Inhibitor (Recombinant).Vet Approved
Food InteractionsNot Available
References
Synthesis ReferenceNot Available
General References
  1. Cicardi M, Zingale L, Zanichelli A, Pappalardo E, Cicardi B: C1 inhibitor: molecular and clinical aspects. Springer Semin Immunopathol. 2005 Nov;27(3):286-98. Epub 2005 Nov 11. [PubMed:16267649 ]
  2. Harpel PC, Cooper NR: Studies on human plasma C1 inactivator-enzyme interactions. I. Mechanisms of interaction with C1s, plasmin, and trypsin. J Clin Invest. 1975 Mar;55(3):593-604. [PubMed:123251 ]
  3. PENSKY J, LEVY LR, LEPOW IH: Partial purification of a serum inhibitor of C'1-esterase. J Biol Chem. 1961 Jun;236:1674-9. [PubMed:13734157 ]
  4. van der Graaf F, Koedam JA, Bouma BN: Inactivation of kallikrein in human plasma. J Clin Invest. 1983 Jan;71(1):149-58. [PubMed:6184384 ]
  5. de Agostini A, Lijnen HR, Pixley RA, Colman RW, Schapira M: Inactivation of factor XII active fragment in normal plasma. Predominant role of C-1-inhibitor. J Clin Invest. 1984 Jun;73(6):1542-9. [PubMed:6725552 ]
  6. Cugno M, Bos I, Lubbers Y, Hack CE, Agostoni A: In vitro interaction of C1-inhibitor with thrombin. Blood Coagul Fibrinolysis. 2001 Jun;12(4):253-60. [PubMed:11460008 ]
  7. Bock SC, Skriver K, Nielsen E, Thogersen HC, Wiman B, Donaldson VH, Eddy RL, Marrinan J, Radziejewska E, Huber R, et al.: Human C1 inhibitor: primary structure, cDNA cloning, and chromosomal localization. Biochemistry. 1986 Jul 29;25(15):4292-301. [PubMed:3756141 ]
External Links
ATC CodesB06AC04 — Conestat alfa
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelDownload (5.72 MB)
MSDSNot Available
Clinical Trials
Clinical Trials
PhaseStatusPurposeConditionsCount
1Not Yet RecruitingTreatmentRenal Failure1
1, 2Active Not RecruitingPreventionDelayed Graft Function / End Stage Renal Disease (ESRD) / Ischemic Reperfusion Injury / Renal Failure1
2CompletedPreventionHereditary Angioedema1
2CompletedTreatmentGenetic Disorders / Hereditary Angioedema1
2RecruitingPreventionAcute Kidney Injury (AKI)1
2RecruitingTreatmentHereditary Angioedema1
2, 3CompletedTreatmentAngioneurotic Edema / Hereditary Angioedema1
3CompletedTreatmentAngioneurotic Edema / Genetic Disorders / Hereditary Angioedema1
Not AvailableRecruitingNot AvailableHereditary Angioedema1
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage forms
FormRouteStrength
Injection, powder, for solutionIntravenous2100 U/1
PricesNot Available
PatentsNot Available
Properties
StateLiquid
Experimental PropertiesNot Available
Taxonomy
DescriptionNot Available
KingdomOrganic Compounds
Super ClassOrganic Acids
ClassCarboxylic Acids and Derivatives
Sub ClassAmino Acids, Peptides, and Analogues
Direct ParentPeptides
Alternative ParentsNot Available
SubstituentsNot Available
Molecular FrameworkNot Available
External DescriptorsNot Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
inhibitor
General Function:
Serine-type peptidase activity
Specific Function:
C1r B chain is a serine protease that combines with C1q and C1s to form C1, the first component of the classical pathway of the complement system.
Gene Name:
C1R
Uniprot ID:
P00736
Uniprot Name:
Complement C1r subcomponent
Molecular Weight:
80118.04 Da
References
  1. Harpel PC, Cooper NR: Studies on human plasma C1 inactivator-enzyme interactions. I. Mechanisms of interaction with C1s, plasmin, and trypsin. J Clin Invest. 1975 Mar;55(3):593-604. [PubMed:123251 ]
Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
inhibitor
General Function:
Serine-type endopeptidase activity
Specific Function:
C1s B chain is a serine protease that combines with C1q and C1r to form C1, the first component of the classical pathway of the complement system. C1r activates C1s so that it can, in turn, activate C2 and C4.
Gene Name:
C1S
Uniprot ID:
P09871
Uniprot Name:
Complement C1s subcomponent
Molecular Weight:
76683.905 Da
References
  1. Harpel PC, Cooper NR: Studies on human plasma C1 inactivator-enzyme interactions. I. Mechanisms of interaction with C1s, plasmin, and trypsin. J Clin Invest. 1975 Mar;55(3):593-604. [PubMed:123251 ]
Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
inhibitor
General Function:
Serine-type endopeptidase activity
Specific Function:
The enzyme cleaves Lys-Arg and Arg-Ser bonds. It activates, in a reciprocal reaction, factor XII after its binding to a negatively charged surface. It also releases bradykinin from HMW kininogen and may also play a role in the renin-angiotensin system by converting prorenin into renin.
Gene Name:
KLKB1
Uniprot ID:
P03952
Uniprot Name:
Plasma kallikrein
Molecular Weight:
71369.205 Da
References
  1. van der Graaf F, Koedam JA, Bouma BN: Inactivation of kallikrein in human plasma. J Clin Invest. 1983 Jan;71(1):149-58. [PubMed:6184384 ]
Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
inhibitor
General Function:
Serine-type endopeptidase activity
Specific Function:
Factor XII is a serum glycoprotein that participates in the initiation of blood coagulation, fibrinolysis, and the generation of bradykinin and angiotensin. Prekallikrein is cleaved by factor XII to form kallikrein, which then cleaves factor XII first to alpha-factor XIIa and then trypsin cleaves it to beta-factor XIIa. Alpha-factor XIIa activates factor XI to factor XIa.
Gene Name:
F12
Uniprot ID:
P00748
Uniprot Name:
Coagulation factor XII
Molecular Weight:
67791.53 Da
References
  1. de Agostini A, Lijnen HR, Pixley RA, Colman RW, Schapira M: Inactivation of factor XII active fragment in normal plasma. Predominant role of C-1-inhibitor. J Clin Invest. 1984 Jun;73(6):1542-9. [PubMed:6725552 ]
Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
inhibitor
General Function:
Thrombospondin receptor activity
Specific Function:
Thrombin, which cleaves bonds after Arg and Lys, converts fibrinogen to fibrin and activates factors V, VII, VIII, XIII, and, in complex with thrombomodulin, protein C. Functions in blood homeostasis, inflammation and wound healing.
Gene Name:
F2
Uniprot ID:
P00734
Uniprot Name:
Prothrombin
Molecular Weight:
70036.295 Da
References
  1. Cugno M, Bos I, Lubbers Y, Hack CE, Agostoni A: In vitro interaction of C1-inhibitor with thrombin. Blood Coagul Fibrinolysis. 2001 Jun;12(4):253-60. [PubMed:11460008 ]
Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
inhibitor
General Function:
Serine-type endopeptidase activity
Specific Function:
Factor XI triggers the middle phase of the intrinsic pathway of blood coagulation by activating factor IX.
Gene Name:
F11
Uniprot ID:
P03951
Uniprot Name:
Coagulation factor XI
Molecular Weight:
70108.56 Da
References
  1. Cicardi M, Zingale L, Zanichelli A, Pappalardo E, Cicardi B: C1 inhibitor: molecular and clinical aspects. Springer Semin Immunopathol. 2005 Nov;27(3):286-98. Epub 2005 Nov 11. [PubMed:16267649 ]
Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
inhibitor
General Function:
Serine-type endopeptidase activity
Specific Function:
Converts the abundant, but inactive, zymogen plasminogen to plasmin by hydrolyzing a single Arg-Val bond in plasminogen. By controlling plasmin-mediated proteolysis, it plays an important role in tissue remodeling and degradation, in cell migration and many other physiopathological events. Plays a direct role in facilitating neuronal migration.
Gene Name:
PLAT
Uniprot ID:
P00750
Uniprot Name:
Tissue-type plasminogen activator
Molecular Weight:
62916.495 Da
References
  1. Cicardi M, Zingale L, Zanichelli A, Pappalardo E, Cicardi B: C1 inhibitor: molecular and clinical aspects. Springer Semin Immunopathol. 2005 Nov;27(3):286-98. Epub 2005 Nov 11. [PubMed:16267649 ]
Drug created on October 22, 2015 15:00 / Updated on June 23, 2017 10:32