Identification

Summary

Conestat alfa is a recombinant C1INH used for the treatment of acute attacks of hereditary angioedema (HAE) due to C1 esterase inhibitor deficiency in adults.

Brand Names
Ruconest
Generic Name
Conestat alfa
DrugBank Accession Number
DB09228
Background

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 allows for increased plasma kallikrein activation and subsequent production of bradykinin. Additionally, C4 and C2 cleavage occurs 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.

Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Other protein based therapies
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
  • Conestat alfa
  • 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

Pharmacology

Indication

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

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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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 allows increased plasma kallikrein activation and subsequent production of bradykinin. Additionally, C4 and C2 cleavage is no longer inhibited allowing 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
Humans
AComplement C1s subcomponent
inhibitor
Humans
APlasma kallikrein
inhibitor
Humans
ACoagulation factor XII
inhibitor
Humans
AProthrombin
inhibitor
Humans
ACoagulation factor XI
inhibitor
Humans
ATissue-type plasminogen activator
inhibitor
Humans
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.

Adverse Effects
Adverseeffects
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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.

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 Conestat alfa.
DesogestrelThe risk or severity of thromboembolism can be increased when Desogestrel is combined with Conestat alfa.
DienogestThe risk or severity of thromboembolism can be increased when Dienogest is combined with Conestat alfa.
DrospirenoneThe risk or severity of thromboembolism can be increased when Drospirenone is combined with Conestat alfa.
DydrogesteroneThe risk or severity of thromboembolism can be increased when Dydrogesterone is combined with Conestat alfa.
Ethynodiol diacetateThe risk or severity of thromboembolism can be increased when Ethynodiol diacetate is combined with Conestat alfa.
EtonogestrelThe risk or severity of thromboembolism can be increased when Etonogestrel is combined with Conestat alfa.
GestrinoneThe risk or severity of thromboembolism can be increased when Gestrinone is combined with Conestat alfa.
Hydroxyprogesterone caproateThe risk or severity of thromboembolism can be increased when Hydroxyprogesterone caproate is combined with Conestat alfa.
LevonorgestrelThe risk or severity of thromboembolism can be increased when Levonorgestrel is combined with Conestat alfa.
Interactions
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Food Interactions
No interactions found.

Products

Products2
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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
RuconestInjection, powder, for solution2100 UIntravenousPharming Group N.V.2020-12-16Not applicableEU flag
RuconestInjection, powder, for solution2100 U/1IntravenousTjoapack Netherlands Bv2016-09-19Not applicableUS flag
RuconestInjection, powder, for solution2100 U/1IntravenousPharming Healthcare Inc.2018-04-01Not applicableUS flag
RuconestInjection, powder, for solution2100 U/1IntravenousBioconnection B.V.2014-09-22Not applicableUS flag
RuconestInjection, powder, for solution2100 UIntravenousPharming Group N.V.2020-12-16Not applicableEU flag
RuconestInjection, powder, for solution2100 U/1IntravenousSantarus, Inc.2014-09-222022-01-18US flag

Categories

ATC Codes
B06AC04 — Conestat alfa
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
Not Available

Chemical Identifiers

UNII
5QS67N4551
CAS number
80295-38-1

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. [Article]
  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. [Article]
  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. [Article]
  4. van der Graaf F, Koedam JA, Bouma BN: Inactivation of kallikrein in human plasma. J Clin Invest. 1983 Jan;71(1):149-58. [Article]
  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. [Article]
  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. [Article]
  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. [Article]
UniProt
P05155
PubChem Substance
347910420
RxNav
1599831
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
C1-inhibitor
FDA label
Download (5.72 MB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4RecruitingTreatmentCoronavirus Disease 2019 (COVID‑19) / Post-Viral Disorder (Disorder) / Post-Viral Fatigue Syndrome1
3CompletedTreatmentAngioneurotic Edema / Genetic Disorders / Hereditary Angioedema (HAE)1
2CompletedPreventionAcute Kidney Injury (AKI)1
2CompletedPreventionHereditary Angioedema (HAE)1
2CompletedTreatmentGenetic Disorders1
2CompletedTreatmentGenetic Disorders / Hereditary Angioedema (HAE)1
2CompletedTreatmentHereditary Angioedema (HAE)1
2RecruitingPreventionNon ST Segment Elevation Myocardial Infarction (NSTEMI)1
2RecruitingTreatmentConfirmed Coronavirus Disease / Coronavirus Disease 2019 (COVID‑19)1
2TerminatedTreatmentCoronavirus Disease 2019 (COVID‑19) / Infections, Coronavirus1

Pharmacoeconomics

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

Properties

State
Liquid
Experimental Properties
Not Available

Targets

Drugtargets2
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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
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. [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 at October 22, 2015 21:00 / Updated at May 07, 2021 21:06