Identification

Name
Conestat alfa
Accession Number
DB09228
Type
Biotech
Groups
Approved
Biologic Classification
Protein Based Therapies
Other protein based therapies
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 structure
Db09228
Protein chemical formula
Not Available
Protein average weight
67000.0 Da
Sequences
Not 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
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
International/Other Brands
Ruconest (Pharming)
Categories
UNII
5QS67N4551
CAS number
80295-38-1

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.

TargetActionsOrganism
AComplement C1r subcomponent
inhibitor
Human
AComplement C1s subcomponent
inhibitor
Human
APlasma kallikrein
inhibitor
Human
ACoagulation factor XII
inhibitor
Human
AProthrombin
inhibitor
Human
ACoagulation factor XI
inhibitor
Human
ATissue-type plasminogen activator
inhibitor
Human
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 distribution
Not Available
Protein binding
Not Available
Metabolism
Not Available
Route of elimination

Elimination half-life was approximately 2.5 hours.

Half life
Not 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 organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteractionDrug group
AllylestrenolAllylestrenol may increase the thrombogenic activities of Conestat alfa.Approved
AltrenogestAltrenogest may increase the thrombogenic activities of Conestat alfa.Vet Approved
ChlorotrianiseneChlorotrianisene may increase the thrombogenic activities of Conestat alfa.Investigational, Withdrawn
Conjugated estrogensConjugated estrogens may increase the thrombogenic activities of Conestat alfa.Approved
DaidzeinDaidzein may increase the thrombogenic activities of Conestat alfa.Experimental
DanazolDanazol may increase the thrombogenic activities of Conestat alfa.Approved
DemegestoneDemegestone may increase the thrombogenic activities of Conestat alfa.Experimental
DesogestrelDesogestrel may increase the thrombogenic activities of Conestat alfa.Approved
DienestrolDienestrol may increase the thrombogenic activities of Conestat alfa.Approved, Investigational
DienogestDienogest may increase the thrombogenic activities of Conestat alfa.Approved
DiethylstilbestrolDiethylstilbestrol may increase the thrombogenic activities of Conestat alfa.Approved, Investigational
DihydrotestosteroneDihydrotestosterone may increase the thrombogenic activities of Conestat alfa.Illicit
DydrogesteroneDydrogesterone may increase the thrombogenic activities of Conestat alfa.Approved, Investigational, Withdrawn
EpimestrolEpimestrol may increase the thrombogenic activities of Conestat alfa.Experimental
EquolEquol may increase the thrombogenic activities of Conestat alfa.Investigational
EstradiolEstradiol may increase the thrombogenic activities of Conestat alfa.Approved, Investigational, Vet Approved
EstriolEstriol may increase the thrombogenic activities of Conestat alfa.Approved, Investigational, Vet Approved
Estrogens, esterifiedEstrogens, esterified may increase the thrombogenic activities of Conestat alfa.Approved
EstroneEstrone may increase the thrombogenic activities of Conestat alfa.Approved
Ethinyl EstradiolEthinyl Estradiol may increase the thrombogenic activities of Conestat alfa.Approved
EthynodiolEthynodiol may increase the thrombogenic activities of Conestat alfa.Experimental
EtonogestrelEtonogestrel may increase the thrombogenic activities of Conestat alfa.Approved, Investigational
FluoxymesteroneFluoxymesterone may increase the thrombogenic activities of Conestat alfa.Approved, Illicit
GenisteinGenistein may increase the thrombogenic activities of Conestat alfa.Investigational
GestodeneGestodene may increase the thrombogenic activities of Conestat alfa.Approved, Investigational
GestonoroneGestonorone may increase the thrombogenic activities of Conestat alfa.Experimental
GestrinoneGestrinone may increase the thrombogenic activities of Conestat alfa.Approved
GLPG-0492GLPG-0492 may increase the thrombogenic activities of Conestat alfa.Investigational
HexestrolHexestrol may increase the thrombogenic activities of Conestat alfa.Withdrawn
Hydroxyprogesterone caproateHydroxyprogesterone caproate may increase the thrombogenic activities of Conestat alfa.Approved
LevonorgestrelLevonorgestrel may increase the thrombogenic activities of Conestat alfa.Approved, Investigational
MedrogestoneMedrogestone may increase the thrombogenic activities of Conestat alfa.Approved
Medroxyprogesterone acetateMedroxyprogesterone acetate may increase the thrombogenic activities of Conestat alfa.Approved, Investigational
Megestrol acetateMegestrol acetate may increase the thrombogenic activities of Conestat alfa.Approved, Vet Approved
MesteroloneMesterolone may increase the thrombogenic activities of Conestat alfa.Experimental
MestranolMestranol may increase the thrombogenic activities of Conestat alfa.Approved
MethallenestrilMethallenestril may increase the thrombogenic activities of Conestat alfa.Experimental
MethylestrenoloneMethylestrenolone may increase the thrombogenic activities of Conestat alfa.Experimental
MethyltestosteroneMethyltestosterone may increase the thrombogenic activities of Conestat alfa.Approved
MoxestrolMoxestrol may increase the thrombogenic activities of Conestat alfa.Experimental
NandroloneNandrolone may increase the thrombogenic activities of Conestat alfa.Experimental, Investigational
Nandrolone decanoateNandrolone decanoate may increase the thrombogenic activities of Conestat alfa.Approved, Illicit
NomegestrolNomegestrol may increase the thrombogenic activities of Conestat alfa.Approved
NorethisteroneNorethisterone may increase the thrombogenic activities of Conestat alfa.Approved
NorgestrienoneNorgestrienone may increase the thrombogenic activities of Conestat alfa.Experimental
OxandroloneOxandrolone may increase the thrombogenic activities of Conestat alfa.Approved, Investigational
OxymetholoneOxymetholone may increase the thrombogenic activities of Conestat alfa.Approved, Illicit
Polyestradiol phosphatePolyestradiol phosphate may increase the thrombogenic activities of Conestat alfa.Approved
ProgesteroneProgesterone may increase the thrombogenic activities of Conestat alfa.Approved, Vet Approved
PromegestonePromegestone may increase the thrombogenic activities of Conestat alfa.Experimental
PromestrienePromestriene may increase the thrombogenic activities of Conestat alfa.Investigational
QuinestrolQuinestrol may increase the thrombogenic activities of Conestat alfa.Approved
SecoisolariciresinolSecoisolariciresinol may increase the thrombogenic activities of Conestat alfa.Investigational
StanozololStanozolol may increase the thrombogenic activities of Conestat alfa.Approved, Vet Approved
Synthetic Conjugated Estrogens, ASynthetic Conjugated Estrogens, A may increase the thrombogenic activities of Conestat alfa.Approved
Synthetic Conjugated Estrogens, BSynthetic Conjugated Estrogens, B may increase the thrombogenic activities of Conestat alfa.Approved
TestosteroneTestosterone may increase the thrombogenic activities of Conestat alfa.Approved, Investigational
Testosterone PropionateTestosterone Propionate may increase the thrombogenic activities of Conestat alfa.Approved, Vet Approved
TiboloneTibolone may increase the thrombogenic activities of Conestat alfa.Approved, Investigational
ZeranolZeranol may increase the thrombogenic activities of Conestat alfa.Vet Approved
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
347910420
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
C1-inhibitor
ATC Codes
B06AC04 — Conestat alfa
FDA label
Download (5.72 MB)

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

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Injection, powder, for solutionIntravenous2100 U/1
Prices
Not Available
Patents
Not Available

Properties

State
Liquid
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
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 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 October 22, 2015 15:00 / Updated on November 06, 2017 06:46