Identification
NameHuman C1-esterase inhibitor
Accession NumberDB06404
TypeBiotech
GroupsApproved
Description

C1 Esterase Inhibitor (Human) is composed of purified endogenous complement component-1 esterase inhibitor (hC1INH) isolated from human plasma. 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 Cyrinze (FDA), this drug is indicated for routine prophylaxis against angioedema attacks in adolescent and adult patients with Hereditary Angioedema (HAE), a human genetic disorder caused by a shortage of C1 inhibitor activity that results in an overreaction of the immune system. The disease is characterized by acute attacks of painful and in some cases fatal swelling of several soft tissues (edema), which may last up to five days when untreated.

In June 2017 the FDA approved a formulation of human C1-esterase inhibitor for subcutaneous administration under the tradename Haegarda.

Protein structureDb06404
Related Articles
Protein chemical formulaNot Available
Protein average weightNot Available
SequencesNot Available
Synonyms
C1 Esterase Inhibitor (Human)
C1 inhibitor
C1 inhibitor (human)
C1 inhibitor human
C1-esterase inhibitor, human
C1-inhibiting factor
C1-inhibitor, plasma derived
Human C1 inhibitor
Human C1-esterase inhibitor
Plasma protease C1 inhibitor
External IDs RVG-19303
Product Ingredients Not Available
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
BerinertKitCsl Behring2011-12-22Not applicableUs
Berinert 1500Kit; Powder, for solution1500 unitIntravenousCsl Behring2015-05-06Not applicableCanada
Berinert 500Kit; Powder, for solution500 unitIntravenousCsl Behring2010-10-06Not applicableCanada
CinryzeInjection, powder, lyophilized, for solution500 [iU]/5mLIntravenousViropharma Biologics Inc2008-12-01Not applicableUs
CinryzePowder, for solution500 unitIntravenousViropharma Biologics Inc2016-03-08Not applicableCanada
CinryzeInjection, powder, for solution500 UIntravenousShire Services Bvba2011-06-15Not applicableEu
Haegarda C1 Esterase Inhibitor Subcutaneous (human)KitCsl Behring2017-06-22Not applicableUs
Haegarda C1 Esterase Inhibitor Subcutaneous (human)KitCsl Behring2017-06-22Not applicableUs
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International BrandsNot Available
Brand mixturesNot Available
Categories
UNII6KIC4BB60G
CAS numberNot Available
Pharmacology
Indication

For routine prophylaxis against angioedema attacks in adolescent and adult patients with Hereditary Angioedema (HAE).

Structured Indications
Pharmacodynamics

In clinical studies, intravenous administration demonstrated an increase in plasma levels of C1 inhibitor within approximately one hour or less of administration. Biological activity was shown in 35 subjects by the subsequent increase in plasma C4 levels from an average of C4 8.1 mg/mL at baseline to C4 8.6 mg/mL 12 hours after infusion.

Mechanism of action

C1 inhibitor is a normal constituent of human blood and is one of the serine proteinase inhibitors (serpins). The primary function of C1 inhibitor is to regulate the activation of the complement and intrinsic coagulation (contact system) pathway. C1 inhibitor also regulates the fibrinolytic system. Regulation of these systems is performed through the formation of complexes between the proteinases and the inhibitor, resulting in inactivation of both and consumption of the C1 inhibitor. HAE patients have low levels of endogenous or functional C1 inhibitor. Although the events that induce attacks of angioedema in HAE patients are not well defined, it is thought by some that increased vascular permeability and the clinical manifestation of HAE attacks are primarily mediated through contact system activation. Suppression of contact system activation by C1 inhibitor through the inactivation of plasma kallikrein and factor XIIa is thought to modulate this vascular permeability by preventing the generation of bradykinin1. Administration of C1 Esterase Inhibitor increases plasma levels of C1 inhibitor activity.

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
ProthrombinProteinunknown
inhibitor
HumanP00734 details
Coagulation factor XIProteinyes
inhibitor
HumanP03951 details
Tissue-type plasminogen activatorProteinyes
inhibitor
HumanP00750 details
Related Articles
Absorption

Cmax was found to be 0.68 units/mL and Tmax was found to be 3.9 hr after administration of a single dose. Tmax for subcutaneous administration is 48 hrs and subcutaneous bioavalability is 39.7% [A19661].

Volume of distributionNot Available
Protein bindingNot Available
MetabolismNot Available
Route of eliminationNot Available
Half life

56 hours (range 11 to 108 hours) for a single dose and 62 hours (range 16 to 152 hours) for the double dose. Subcutaneous administration produces a half life of 199.6 hours [A19661].

Clearance

0.85 mL/min (single dose)

Toxicity

The most common adverse reactions observed were headache, nausea, rash and vomiting.

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

Because this product is made from human blood, it may carry a risk of transmitting infectious agents, e.g. viruses, and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent.

Affected organisms
  • Humans and other mammals
PathwaysNot Available
Pharmacogenomic Effects/ADRs Not Available
Interactions
Drug Interactions
DrugInteractionDrug group
AllylestrenolAllylestrenol may increase the thrombogenic activities of C1 Esterase Inhibitor (Human).Approved
BazedoxifeneBazedoxifene may increase the thrombogenic activities of C1 Esterase Inhibitor (Human).Approved, Investigational
BCG vaccineThe therapeutic efficacy of Bcg can be decreased when used in combination with C1 Esterase Inhibitor (Human).Investigational
ChlorotrianiseneChlorotrianisene may increase the thrombogenic activities of C1 Esterase Inhibitor (Human).Withdrawn
Conjugated estrogensConjugated Equine Estrogens may increase the thrombogenic activities of C1 Esterase Inhibitor (Human).Approved
DenosumabThe risk or severity of adverse effects can be increased when Denosumab is combined with C1 Esterase Inhibitor (Human).Approved
DesogestrelDesogestrel may increase the thrombogenic activities of C1 Esterase Inhibitor (Human).Approved
DienestrolDienestrol may increase the thrombogenic activities of C1 Esterase Inhibitor (Human).Approved
DienogestDienogest may increase the thrombogenic activities of C1 Esterase Inhibitor (Human).Approved
DiethylstilbestrolDiethylstilbestrol may increase the thrombogenic activities of C1 Esterase Inhibitor (Human).Approved
DihydrotestosteroneDihydrotestosterone may increase the thrombogenic activities of C1 Esterase Inhibitor (Human).Illicit
DrospirenoneDrospirenone may increase the thrombogenic activities of C1 Esterase Inhibitor (Human).Approved
DydrogesteroneDydrogesterone may increase the thrombogenic activities of C1 Esterase Inhibitor (Human).Approved, Withdrawn
EquolS Equol may increase the thrombogenic activities of C1 Esterase Inhibitor (Human).Investigational
EstradiolEstradiol may increase the thrombogenic activities of C1 Esterase Inhibitor (Human).Approved, Investigational, Vet Approved
EstriolEstriol may increase the thrombogenic activities of C1 Esterase Inhibitor (Human).Approved, Vet Approved
EstroneEstrone may increase the thrombogenic activities of C1 Esterase Inhibitor (Human).Approved
Ethinyl EstradiolEthinyl Estradiol may increase the thrombogenic activities of C1 Esterase Inhibitor (Human).Approved
Ethynodiol diacetateEthynodiol diacetate may increase the thrombogenic activities of C1 Esterase Inhibitor (Human).Approved
EtonogestrelEtonogestrel may increase the thrombogenic activities of C1 Esterase Inhibitor (Human).Approved, Investigational
FingolimodC1 Esterase Inhibitor (Human) may increase the immunosuppressive activities of Fingolimod.Approved, Investigational
FluoxymesteroneFluoxymesterone may increase the thrombogenic activities of C1 Esterase Inhibitor (Human).Approved, Illicit
G17DTThe risk or severity of adverse effects can be increased when C1 Esterase Inhibitor (Human) is combined with G17DT.Investigational
GenisteinGenistein may increase the thrombogenic activities of C1 Esterase Inhibitor (Human).Investigational
GestodeneGestodene may increase the thrombogenic activities of C1 Esterase Inhibitor (Human).Approved
GestrinoneGestrinone may increase the thrombogenic activities of C1 Esterase Inhibitor (Human).Approved
HexestrolHexestrol may increase the thrombogenic activities of C1 Esterase Inhibitor (Human).Withdrawn
Hydroxyprogesterone caproateHydroxyprogesterone caproate may increase the thrombogenic activities of C1 Esterase Inhibitor (Human).Approved
INGN 201The risk or severity of adverse effects can be increased when C1 Esterase Inhibitor (Human) is combined with INGN 201.Investigational
INGN 225The risk or severity of adverse effects can be increased when C1 Esterase Inhibitor (Human) is combined with INGN 225.Investigational
LeflunomideThe risk or severity of adverse effects can be increased when C1 Esterase Inhibitor (Human) is combined with Leflunomide.Approved, Investigational
LevonorgestrelLevonorgestrel may increase the thrombogenic activities of C1 Esterase Inhibitor (Human).Approved, Investigational
LynestrenolLynestrenol may increase the thrombogenic activities of C1 Esterase Inhibitor (Human).Investigational
MedrogestoneMedrogestone may increase the thrombogenic activities of C1 Esterase Inhibitor (Human).Approved
Medroxyprogesterone acetateMedroxyprogesterone acetate may increase the thrombogenic activities of C1 Esterase Inhibitor (Human).Approved, Investigational
Megestrol acetateMegestrol acetate may increase the thrombogenic activities of C1 Esterase Inhibitor (Human).Approved, Vet Approved
MestranolMestranol may increase the thrombogenic activities of C1 Esterase Inhibitor (Human).Approved
MethallenestrilMethallenestril may increase the thrombogenic activities of C1 Esterase Inhibitor (Human).Experimental
MethyltestosteroneMethyltestosterone may increase the thrombogenic activities of C1 Esterase Inhibitor (Human).Approved
NatalizumabThe risk or severity of adverse effects can be increased when C1 Esterase Inhibitor (Human) is combined with Natalizumab.Approved, Investigational
NorethisteroneNorethisterone may increase the thrombogenic activities of C1 Esterase Inhibitor (Human).Approved
OxandroloneOxandrolone may increase the thrombogenic activities of C1 Esterase Inhibitor (Human).Approved, Investigational
OxymetholoneOxymetholone may increase the thrombogenic activities of C1 Esterase Inhibitor (Human).Approved, Illicit
PimecrolimusThe risk or severity of adverse effects can be increased when Pimecrolimus is combined with C1 Esterase Inhibitor (Human).Approved, Investigational
ProgesteroneProgesterone may increase the thrombogenic activities of C1 Esterase Inhibitor (Human).Approved, Vet Approved
PromestrienePromestriene may increase the thrombogenic activities of C1 Esterase Inhibitor (Human).Investigational
QuinestrolQuinestrol may increase the thrombogenic activities of C1 Esterase Inhibitor (Human).Approved
RindopepimutThe risk or severity of adverse effects can be increased when C1 Esterase Inhibitor (Human) is combined with CDX-110.Investigational
RoflumilastRoflumilast may increase the immunosuppressive activities of C1 Esterase Inhibitor (Human).Approved
SecoisolariciresinolSecoisolariciresinol may increase the thrombogenic activities of C1 Esterase Inhibitor (Human).Investigational
Sipuleucel-TThe therapeutic efficacy of Sipuleucel-T can be decreased when used in combination with C1 Esterase Inhibitor (Human).Approved
SRP 299The risk or severity of adverse effects can be increased when C1 Esterase Inhibitor (Human) is combined with SRP 299.Investigational
StanozololStanozolol may increase the thrombogenic activities of C1 Esterase Inhibitor (Human).Approved, Vet Approved
Synthetic Conjugated Estrogens, ASynthetic Conjugated Estrogens, A may increase the thrombogenic activities of C1 Esterase Inhibitor (Human).Approved
Synthetic Conjugated Estrogens, BSynthetic Conjugated Estrogens, B may increase the thrombogenic activities of C1 Esterase Inhibitor (Human).Approved
TacrolimusThe risk or severity of adverse effects can be increased when Tacrolimus is combined with C1 Esterase Inhibitor (Human).Approved, Investigational
TestosteroneTestosterone may increase the thrombogenic activities of C1 Esterase Inhibitor (Human).Approved, Investigational
TiboloneTibolone may increase the thrombogenic activities of C1 Esterase Inhibitor (Human).Approved
TofacitinibC1 Esterase Inhibitor (Human) may increase the immunosuppressive activities of Tofacitinib.Approved, Investigational
TrastuzumabTrastuzumab may increase the neutropenic activities of C1 Esterase Inhibitor (Human).Approved, Investigational
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 CodesB06AC01 — C1-inhibitor, plasma derived
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelDownload (379 KB)
MSDSNot Available
Clinical Trials
Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentHereditary Angioedema Types I and II1
1CompletedTreatmentNeuromyelitis Optica1
1Not Yet RecruitingTreatmentRenal Failure1
1, 2Active Not RecruitingPreventionDelayed Graft Function / End Stage Renal Disease (ESRD) / Ischemic Reperfusion Injury / Renal Failure1
1, 2CompletedTreatmentTransplantation, Kidney1
2CompletedNot AvailableHereditary Angioedema2
2CompletedPreventionHereditary Angioedema1
2CompletedTreatmentHereditary Angioedema1
2CompletedTreatmentRejection, Transplant1
2Enrolling by InvitationTreatmentAntibody Mediated Rejection of Kidney Transplant1
2, 3CompletedTreatmentHereditary Angioedema1
3RecruitingTreatmentAcute ACE-induced Angioedema1
3RecruitingTreatmentAcute Antibody-Mediated Rejection (AMR)1
4CompletedPreventionHereditary Angioedema1
4CompletedTreatmentHereditary Angioedema Types I and II1
4RecruitingTreatmentAsthma Bronchial1
Not AvailableCompletedNot AvailableIncludes: Hereditary Angioedema1
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage forms
FormRouteStrength
Kit
Kit; powder, for solutionIntravenous1500 unit
Kit; powder, for solutionIntravenous500 unit
Injection, powder, for solutionIntravenous500 U
Injection, powder, lyophilized, for solutionIntravenous500 [iU]/5mL
Powder, for solutionIntravenous500 unit
PricesNot Available
PatentsNot Available
Properties
StateSolid
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
unknown
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 March 19, 2008 10:29 / Updated on June 23, 2017 09:42