Human C1-esterase inhibitor

Identification

Summary

Human C1-esterase inhibitor is a C1 inhibitor used to prevent angioedema attacks associated with hereditary angioedema.

Brand Names
Berinert, Cinryze, Haegarda
Generic Name
Human C1-esterase inhibitor
DrugBank Accession Number
DB06404
Background

C1 Esterase Inhibitor (Human) is composed of purified endogenous complement component-1 esterase inhibitor (hC1INH) isolated from human plasma.3,4,6 The primary function of endogenous C1INH is to regulate the activation of the complement and contact system pathways.3,4,6

This drug is indicated for prophylaxis and treatment of Hereditary Angioedema (HAE), a human genetic disorder caused by a shortage of C1 inhibitor activity that results in an overreaction of the immune system.3,4,6 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.3,4,6

Type
Biotech
Groups
Approved
Biologic Classification
Protein Based Therapies
Other protein based therapies
Protein Structure
Db06404
Protein Chemical Formula
Not Available
Protein Average Weight
68000.0 Da
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

Pharmacology

Indication

C1 esterase inhibitors are indicated for the prophylaxis and treatment of acute attacks of hereditary angioedema in patients at least 6 years old.3,4,5

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

The C1 esterase inhibitor treats and prevents attacks of hereditary angioedema.4 It has a long duration of action as it is given every 3-4 days prophylactically.3 Patients should be counselled regarding the risk of hypersensitivity reactions as well as arterial and venous thromboemboli.3,4

Mechanism of action

The C1 esterase inhibitor binds to proteins such as C1s, kallikrein, factor XIIa, and XIa and irreversibly inactivates them.3,4 Patients with hereditary angioedema have low levels of C1 esterase inhibitors.3,4 By providing patients with C1 esterase inhibitors, this may prevent contact system activation, which prevents increases in vascular permeability.3,4 Manifestations of hereditary angioedema may be prevented by preventing increases in vascular permeability.3,4

TargetActionsOrganism
AComplement C1r subcomponent
inhibitor
Humans
AComplement C1s subcomponent
inhibitor
Humans
APlasma kallikrein
inhibitor
Humans
ACoagulation factor XII
inhibitor
Humans
UProthrombin
inhibitor
Humans
ACoagulation factor XI
inhibitor
Humans
ATissue-type plasminogen activator
inhibitor
Humans
Absorption

A 50 IU/kg dose reaches a Cmax of 1.2 ± 0.2 IU/mL, with a Tmax of 0.31 ± 0.10 hours, and an AUC of 3.3 ± 1.0 IU*h/mL.4 A 100 IU/kg dose reaches a Cmax of 2.3 ± 0.2 IU/mL, with a Tmax of 0.31 ± 0.10 hours, and an AUC of 10.6 ± 2.5 IU*h/mL.4

Volume of distribution

The volume of distribution at steady state of a 50 IU/kg dose is 3.0 ± 0.9 L.4

Protein binding

Data regarding the protein binding of the C1 esterase inhibitor is not readily available.3,4

Metabolism

Protein drugs are expected to be degraded by proteases and other catalytic enzymes to smaller peptides and amino acids.1

Route of elimination

After nonspecific proteolysis, the amino acids from protein drugs are reused for protein synthesis or further broken down and eliminated by the kidneys.1

Half-life

The half life of a 50 IU/kg dose is 2.4 ± 0.6 h, while the half life of a 100 IU/kg dose is 2.7 ± 0.3 h.4 Subcutaneous administration produces a half life of 199.6 hours.2

Clearance

The clearance of a 50 IU/kg dose is 1207 ± 414 mL/h, while the clearance of a 100 IU/kg dose is 781 ± 147 mL/h.4

Adverse Effects
Medicalerrors
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Toxicity

Data regarding overdoses in humans are not readily available.4 A study in monkeys showed doses above the recommended human dose resulted in temporarily increased liver enzymes such as AST and ALP.4

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
Cyproterone acetateThe risk or severity of thromboembolism can be increased when Cyproterone acetate is combined with Human C1-esterase inhibitor.
DesogestrelThe risk or severity of thromboembolism can be increased when Desogestrel is combined with Human C1-esterase inhibitor.
DienogestThe risk or severity of thromboembolism can be increased when Dienogest is combined with Human C1-esterase inhibitor.
DrospirenoneThe risk or severity of thromboembolism can be increased when Drospirenone is combined with Human C1-esterase inhibitor.
DydrogesteroneThe risk or severity of thromboembolism can be increased when Dydrogesterone is combined with Human C1-esterase inhibitor.
Ethynodiol diacetateThe risk or severity of thromboembolism can be increased when Ethynodiol diacetate is combined with Human C1-esterase inhibitor.
EtonogestrelThe risk or severity of thromboembolism can be increased when Etonogestrel is combined with Human C1-esterase inhibitor.
GestrinoneThe risk or severity of thromboembolism can be increased when Gestrinone is combined with Human C1-esterase inhibitor.
Hydroxyprogesterone caproateThe risk or severity of thromboembolism can be increased when Hydroxyprogesterone caproate is combined with Human C1-esterase inhibitor.
LevonorgestrelThe risk or severity of thromboembolism can be increased when Levonorgestrel is combined with Human C1-esterase inhibitor.
Interactions
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Food Interactions
No interactions found.

Products

Products
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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Berinert500 [iU]/10mLIntravenousCSL Behring GmbH2011-12-22Not applicableUS flag
Berinert 1500Kit; Powder, for solution1500 unit / vialIntravenousCsl Behring2015-05-06Not applicableCanada flag
Berinert 500Kit; Powder, for solution500 unit / vialIntravenousCsl Behring2010-10-06Not applicableCanada flag
CinryzeInjection, powder, for solution500 UIntravenousShire Services Bvba2016-09-08Not applicableEU flag
CinryzePowder, for solution500 unit / vialIntravenousTakeda2016-03-08Not applicableCanada flag
CinryzeInjection500 [iU]/5mLIntravenousViropharma Biologics Llc2021-01-15Not applicableUS flag
CinryzeInjection, powder, lyophilized, for solution500 [iU]/5mLIntravenousViropharma Biologics Llc2008-12-01Not applicableUS flag
HaegardaKit; Powder, for solution3000 unit / vialSubcutaneousCsl Behring2020-01-23Not applicableCanada flag
HaegardaKit; Powder, for solution2000 unit / vialSubcutaneousCsl Behring2020-01-23Not applicableCanada flag
HAEGARDA C1 Esterase Inhibitor Subcutaneous (Human)Kit; Solution2000 [iU]/4mLSubcutaneousCSL Behring GmbH2017-06-22Not applicableUS flag

Categories

ATC Codes
B06AC01 — C1-inhibitor, plasma derived
Drug Categories
Chemical TaxonomyProvided by Classyfire
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
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
6KIC4BB60G
CAS number
Not Available

References

General References
  1. Katsila T, Siskos AP, Tamvakopoulos C: Peptide and protein drugs: the study of their metabolism and catabolism by mass spectrometry. Mass Spectrom Rev. 2012 Jan-Feb;31(1):110-33. doi: 10.1002/mas.20340. Epub 2011 Jun 22. [Article]
  2. Martinez-Saguer I, Cicardi M, Suffritti C, Rusicke E, Aygoren-Pursun E, Stoll H, Rossmanith T, Feussner A, Kalina U, Kreuz W: Pharmacokinetics of plasma-derived C1-esterase inhibitor after subcutaneous versus intravenous administration in subjects with mild or moderate hereditary angioedema: the PASSION study. Transfusion. 2014 Jun;54(6):1552-61. doi: 10.1111/trf.12501. Epub 2013 Nov 24. [Article]
  3. FDA Approved Blood Products: Cinryze C1 Esterase Inhibitor Intravenous Injection [Link]
  4. FDA Approved Blood Products: Ruconest C1 Esterase Inhibitor Intravenous Injection [Link]
  5. FDA: Supplemental Approval of C1 Esterase Inhibitors [Link]
  6. FDA Approved Blood Products: Haegarda C1 Esterase Inhibitor Subcutaneous Injection [Link]
UniProt
P05155
PubChem Substance
347910350
RxNav
809864
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
C1-inhibitor
FDA label
Download (379 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedPreventionHereditary Angioedema1
4CompletedTreatmentHereditary Angioedema Types I and II1
4TerminatedTreatmentAsthma1
3CompletedNot AvailableHereditary Angioedema1
3CompletedPreventionHereditary Angioedema (HAE)1
3CompletedTreatmentAcute ACE-induced Angioedema1
3CompletedTreatmentAngioedema1
3CompletedTreatmentHereditary Angioedema1
3CompletedTreatmentHereditary Angioedema (HAE)1
3TerminatedTreatmentAcute Antibody-Mediated Rejection (AMR)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, powder, for solutionIntravenous
Kit; powder, for solutionIntravenous1500 unit / vial
Kit; powder, for solutionIntravenous500 unit / vial
InjectionIntravenous500 [iU]/5mL
Injection, powder, for solutionIntravenous500 U
Injection, powder, lyophilized, for solutionIntravenous500 [iU]/5mL
Powder, for solutionIntravenous500 unit / vial
Injection, solutionIntravenous
Kit; powder, for solutionSubcutaneous2000 unit / vial
Kit; powder, for solutionSubcutaneous3000 unit / vial
Kit; solutionSubcutaneous2000 [iU]/4mL
Kit; solutionSubcutaneous3000 [iU]/6mL
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available

Targets

Drugtargets
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Kind
Protein
Organism
Humans
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. [Article]
Kind
Protein
Organism
Humans
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. [Article]
Kind
Protein
Organism
Humans
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. [Article]
Kind
Protein
Organism
Humans
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. [Article]
Kind
Protein
Organism
Humans
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. [Article]
Kind
Protein
Organism
Humans
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. [Article]
Kind
Protein
Organism
Humans
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. [Article]

Drug created on March 19, 2008 16:29 / Updated on July 24, 2021 14:58