Human C1-esterase inhibitor

Identification

Name
Human C1-esterase inhibitor
Accession Number
DB06404  (DB05341)
Type
Biotech
Groups
Approved
Biologic Classification
Protein Based Therapies
Other protein based therapies
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 structure
Db06404
Protein chemical formula
Not Available
Protein average weight
Not Available
Sequences
Not Available
Synonyms
  • C1 Esterase Inhibitor (Human)
  • C1 inhibitor
  • C1 inhibitor (human)
  • C1 inhibitor human
  • C1-esterase inhibitor, human
  • C1-INH
  • C1-inhibiting factor
  • C1-inhibitor, plasma derived
  • Human C1 inhibitor
  • Human C1-esterase inhibitor
  • Plasma protease C1 inhibitor
External IDs
RVG-19303
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
BerinertKit500 [iU]/10mLCSL Behring GmbH2011-12-22Not applicableUs
Berinert 1500Kit; Powder, for solution1500 unitIntravenousCsl Behring2015-05-06Not applicableCanada
Berinert 500Kit; Powder, for solution500 unitIntravenousCsl Behring2010-10-06Not applicableCanada
CinryzeInjection, powder, for solution500 UIntravenousShire Services Bvba2011-06-15Not applicableEu
CinryzePowder, for solution500 unitIntravenousViropharma Biologics Inc2016-03-08Not applicableCanada
CinryzeInjection, powder, lyophilized, for solution500 [iU]/5mLIntravenousViropharma Biologics Inc2008-12-01Not applicableUs
HaegardaKit; Powder, for solution2000 unitSubcutaneousCsl BehringNot applicableNot applicableCanada
HaegardaKit; Powder, for solution3000 unitSubcutaneousCsl BehringNot applicableNot applicableCanada
HAEGARDA C1 Esterase Inhibitor Subcutaneous (Human)Kit2000 [iU]/4mLCSL Behring GmbH2017-06-22Not applicableUs
HAEGARDA C1 Esterase Inhibitor Subcutaneous (Human)Kit3000 [iU]/6mLCSL Behring GmbH2017-06-22Not applicableUs
Categories
UNII
6KIC4BB60G
CAS number
Not Available

Pharmacology

Indication

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

Associated Conditions
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.

TargetActionsOrganism
AComplement C1r subcomponent
inhibitor
Human
AComplement C1s subcomponent
inhibitor
Human
APlasma kallikrein
inhibitor
Human
ACoagulation factor XII
inhibitor
Human
UProthrombin
inhibitor
Human
ACoagulation factor XI
inhibitor
Human
ATissue-type plasminogen activator
inhibitor
Human
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 distribution
Not Available
Protein binding
Not Available
Metabolism
Not Available
Route of elimination
Not 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
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
16-BromoepiandrosteroneThe risk or severity of thromboembolism can be increased when 16-Bromoepiandrosterone is combined with Human C1-esterase inhibitor.
19-norandrostenedioneThe risk or severity of thromboembolism can be increased when 19-norandrostenedione is combined with Human C1-esterase inhibitor.
5-androstenedioneThe risk or severity of thromboembolism can be increased when 5-androstenedione is combined with Human C1-esterase inhibitor.
AldosteroneThe risk or severity of thromboembolism can be increased when Aldosterone is combined with Human C1-esterase inhibitor.
AllylestrenolThe risk or severity of thromboembolism can be increased when Allylestrenol is combined with Human C1-esterase inhibitor.
AltrenogestThe risk or severity of thromboembolism can be increased when Altrenogest is combined with Human C1-esterase inhibitor.
AndrostenedioneThe risk or severity of thromboembolism can be increased when Androstenedione is combined with Human C1-esterase inhibitor.
AnecortaveThe risk or severity of thromboembolism can be increased when Anecortave is combined with Human C1-esterase inhibitor.
AtamestaneThe risk or severity of thromboembolism can be increased when Atamestane is combined with Human C1-esterase inhibitor.
Beclomethasone 17-monopropionateThe risk or severity of thromboembolism can be increased when Beclomethasone 17-monopropionate is combined with Human C1-esterase inhibitor.
Food Interactions
Not Available

References

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
UniProt
P05155
PubChem Substance
347910350
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
C1-inhibitor
ATC Codes
B06AC01 — C1-inhibitor, plasma derived
AHFS Codes
  • 92:32.00 — Complement Inhibitors
FDA label
Download (379 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentHereditary Angioedema Types I and II1
1CompletedTreatmentNeuromyelitis Optica1
1Not Yet RecruitingTreatmentRenal Failure1
1, 2CompletedPreventionDelayed 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
3RecruitingTreatmentAntibody-mediated Rejection1
4CompletedPreventionHereditary Angioedema1
4CompletedTreatmentHereditary Angioedema Types I and II1
4RecruitingTreatmentAsthma Bronchial1
Not AvailableCompletedNot AvailableIncludes: Hereditary Angioedema1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Kit500 [iU]/10mL
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
Kit; powder, for solutionSubcutaneous2000 unit
Kit; powder, for solutionSubcutaneous3000 unit
Kit2000 [iU]/4mL
Kit3000 [iU]/6mL
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available

Taxonomy

Description
Not Available
Kingdom
Organic Compounds
Super Class
Organic Acids
Class
Carboxylic Acids and Derivatives
Sub Class
Amino Acids, Peptides, and Analogues
Direct Parent
Peptides
Alternative Parents
Not Available
Substituents
Not Available
Molecular Framework
Not Available
External Descriptors
Not 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, activat...
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 an...
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 t...
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 homeostas...
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 t...
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 December 10, 2018 06:10