Antihemophilic Factor (Recombinant), PEGylated

Identification

Name
Antihemophilic Factor (Recombinant), PEGylated
Accession Number
DB09329
Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Blood factors
Description

Antihemophilic Factor (Recombinant), PEGylated, was approved by the FDA in December 2016 as the product Adynovate [Label].

Antihemophilic Factor (Recombinant), PEGylated, is a recombinant full-length human coagulation factor VIII (2,332 amino acids with a molecular weight (MW) of approximately 280 kDa) covalently conjugated with at least one molecule of polyethylene glycol (MW 20 kDa) [Label]. It has been created to increase the half-life of factor VIII, which decreases dose frequency and decreases the occurrence of bleeding events [2], [3], [Label].

PEGylation is the covalent attachment of a polyethylene glycol polymer, called PEG, to a drug or protein. PEGylation decreases factor VIII clearance and allowing for an increased duration of drug circulation in the plasma [7].

Protein chemical formula
Not Available
Protein average weight
284.0 Da
Sequences
Not Available
Synonyms
  • Antihemophilic Factor (Recombinant), PEGylated
  • antihemophilic factor (recombinant), PEGylated-aucl
External IDs
BAY 94-9027
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
AdynovateKit; Powder, for solution2000 unitIntravenousShire Pharma Canada UlcNot applicableNot applicableCanada
AdynovateKit; Powder, for solution250 unitIntravenousShire Pharma Canada UlcNot applicableNot applicableCanada
AdynovateKit; Powder, for solution1000 unitIntravenousShire Pharma Canada UlcNot applicableNot applicableCanada
AdynovateKit; Powder, for solution500 unitIntravenousShire Pharma Canada UlcNot applicableNot applicableCanada
Categories
UNII
Not Available
CAS number
1628187-15-4

Pharmacology

Indication

For the management of hemophilia A (congenital factor VIII deficiency) [Label], [1]. This medication is a human antihemophilic factor indicated in adolescent and adult patients (12 years and older) with hemophilia A (congenital factor VIII deficiency). It is also used for on-demand treatment and control of bleeding and routine prophylaxis of bleeding episodes. It is not indicated for the treatment of von Willebrand disease [Label].

Associated Conditions
Pharmacodynamics

This drug temporarily replaces the missing coagulation factor VIII, required for effective hemostasis in patients with congenital hemophilia A [Label].

Hemophilia A patients have a deficiency of factor VIII, resulting in a prolonged, patient plasma clotting time as demonstrated by the activated partial thromboplastin time (aPTT). Treatment with recombinant factor VIII normalizes the aPTT. Hemophilia A is a sex-linked hereditary disorder of blood coagulation caused by decreased levels of Factor VIII activity, resulting in severe bleeding into the joints, muscles or internal organs, spontaneously/as a result of trauma [18], [6].

Mechanism of action

PEG with Factor VIII effectively increases the molecular weight and size of the protein by creating a hydrophilic cloud around the molecule. This molecular change may reduce the susceptibility of this molecule to proteolytic degradation. It is also believed that PEGylation alters the surface charge of the protein that inhibits receptor-mediated clearance [4]. This drug reduces binding to the LRP1 receptor, which normally clears factor VIII from the circulation [5], [Label].

The plasma levels of Factor VIII are increased with replacement therapy, which allows for a temporary correction of the factor deficiency, thus a correction of the bleeding tendency [18].

TargetActionsOrganism
Avon Willebrand factor
binder
Human
Absorption

AUC0-Inf [IU·h/dL]:

1642 ± 752 in children aged 12 to <18 years [Label] 2264 ± 729 in adults ≥18 years [Label]

Volume of distribution

At steady state: 0.56 ± 0.18 dL/Kg in children aged 12 to <18 years [Label] 0.43 ± 0.11 dL/kg in adults aged ≥18 years [Label]

Protein binding
Not Available
Metabolism
Not Available
Route of elimination
Not Available
Half life

14.69 ± 3.79h for adults aged ≥18 years [Label]

13.43 ± 4.05 for children 12 to <18 years [Label]

Clearance

2.27 ± 0.84 for adults ≥18 years [Label]

3.87 ± 3.31 for children 12 to <18 years [Label]

Toxicity

Common adverse reactions reported in ≥1% of subjects in the clinical studies were headache and nausea [Label].

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe therapeutic efficacy of Antihemophilic Factor (Recombinant), PEGylated can be decreased when used in combination with (R)-warfarin.
(S)-WarfarinThe therapeutic efficacy of Antihemophilic Factor (Recombinant), PEGylated can be decreased when used in combination with (S)-Warfarin.
4-hydroxycoumarinThe therapeutic efficacy of Antihemophilic Factor (Recombinant), PEGylated can be decreased when used in combination with 4-hydroxycoumarin.
AbacavirAbacavir may decrease the excretion rate of Antihemophilic Factor (Recombinant), PEGylated which could result in a higher serum level.
AbciximabThe therapeutic efficacy of Antihemophilic Factor (Recombinant), PEGylated can be decreased when used in combination with Abciximab.
Abicipar PegolThe therapeutic efficacy of Abicipar Pegol can be decreased when used in combination with Antihemophilic Factor (Recombinant), PEGylated.
AcarboseAcarbose may decrease the excretion rate of Antihemophilic Factor (Recombinant), PEGylated which could result in a higher serum level.
AceclofenacAceclofenac may decrease the excretion rate of Antihemophilic Factor (Recombinant), PEGylated which could result in a higher serum level.
AcemetacinAcemetacin may decrease the excretion rate of Antihemophilic Factor (Recombinant), PEGylated which could result in a higher serum level.
AcenocoumarolThe therapeutic efficacy of Antihemophilic Factor (Recombinant), PEGylated can be decreased when used in combination with Acenocoumarol.
Food Interactions
Not Available

References

General References
  1. Dunn AL, Ahuja SP, Mullins ES: Real-world experience with use of Antihemophilic Factor (Recombinant), PEGylated for prophylaxis in severe haemophilia A. Haemophilia. 2018 Jan 23. doi: 10.1111/hae.13403. [PubMed:29359417]
  2. Wynn TT, Gumuscu B: Potential role of a new PEGylated recombinant factor VIII for hemophilia A. J Blood Med. 2016 Jun 20;7:121-8. doi: 10.2147/JBM.S82457. eCollection 2016. [PubMed:27382347]
  3. Tiede A, Brand B, Fischer R, Kavakli K, Lentz SR, Matsushita T, Rea C, Knobe K, Viuff D: Enhancing the pharmacokinetic properties of recombinant factor VIII: first-in-human trial of glycoPEGylated recombinant factor VIII in patients with hemophilia A. J Thromb Haemost. 2013 Apr;11(4):670-8. doi: 10.1111/jth.12161. [PubMed:23398640]
  4. Chavin SI: Factor VIII: structure and function in blood clotting. Am J Hematol. 1984 Apr;16(3):297-306. [PubMed:6424437]
  5. Bovenschen N, van Dijk KW, Havekes LM, Mertens K, van Vlijmen BJ: Clearance of coagulation factor VIII in very low-density lipoprotein receptor knockout mice. Br J Haematol. 2004 Sep;126(5):722-5. doi: 10.1111/j.1365-2141.2004.05093.x. [PubMed:15327526]
  6. Coppola A, Di Capua M, Di Minno MN, Di Palo M, Marrone E, Ierano P, Arturo C, Tufano A, Cerbone AM: Treatment of hemophilia: a review of current advances and ongoing issues. J Blood Med. 2010;1:183-95. doi: 10.2147/JBM.S6885. Epub 2010 Aug 30. [PubMed:22282697]
  7. Adynovate Pro [Link]
  8. Adynovate assessment report EMA [Link]
  9. Safety and prolonged activity of recombinant factor VIII Fc fusion protein in hemophilia A patients [Link]
  10. Potential role of a new PEGylated recombinant factor VIII for hemophilia A [Link]
  11. Potential role of a new PEGylated recombinant factor VIII for hemophilia A [Link]
  12. PEGylation of a Factor VIII–Phosphatidylinositol Complex: Pharmacokinetics and Immunogenicity in Hemophilia A Mice [Link]
  13. Pegylated, full-length, recombinant factor VIII for prophylactic and on-demand treatment of severe hemophilia A [Link]
  14. Non-clinical pharmacokinetics and pharmacodynamics of rVIII-SingleChain, a novel recombinant single-chain factor VIII [Link]
  15. Antihemophilic Factor (Recombinant [Pegylated]) [Link]
  16. EMA label Adate [Link]
  17. F8 gene coagulation factor VIII [Link]
  18. Advate Product Monograph [Link]
External Links
PubChem Substance
347910440
AHFS Codes
  • 20:28.16 — Hemostatics
FDA label
Download (474 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedBasic ScienceHemophilia A1
2RecruitingTreatmentHemophilia1
3Active Not RecruitingPreventionHemophilia A1
3CompletedTreatmentHemophilia A1
3RecruitingTreatmentHemophilia A1
Not AvailableRecruitingNot AvailableHemophilia1
Not AvailableRecruitingNot AvailableHemophilia A1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Kit; powder, for solutionIntravenous1000 unit
Kit; powder, for solutionIntravenous2000 unit
Kit; powder, for solutionIntravenous250 unit
Kit; powder, for solutionIntravenous500 unit
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
Binder
General Function
Protein n-terminus binding
Specific Function
Important in the maintenance of hemostasis, it promotes adhesion of platelets to the sites of vascular injury by forming a molecular bridge between sub-endothelial collagen matrix and platelet-surf...
Gene Name
VWF
Uniprot ID
P04275
Uniprot Name
von Willebrand factor
Molecular Weight
309261.83 Da
References
  1. Chavin SI: Factor VIII: structure and function in blood clotting. Am J Hematol. 1984 Apr;16(3):297-306. [PubMed:6424437]
  2. Tiede A, Brand B, Fischer R, Kavakli K, Lentz SR, Matsushita T, Rea C, Knobe K, Viuff D: Enhancing the pharmacokinetic properties of recombinant factor VIII: first-in-human trial of glycoPEGylated recombinant factor VIII in patients with hemophilia A. J Thromb Haemost. 2013 Apr;11(4):670-8. doi: 10.1111/jth.12161. [PubMed:23398640]
  3. F8 gene coagulation factor VIII [Link]
  4. Adynovate FDA label [File]

Carriers

Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Protein n-terminus binding
Specific Function
Important in the maintenance of hemostasis, it promotes adhesion of platelets to the sites of vascular injury by forming a molecular bridge between sub-endothelial collagen matrix and platelet-surf...
Gene Name
VWF
Uniprot ID
P04275
Uniprot Name
von Willebrand factor
Molecular Weight
309261.83 Da
References
  1. Chavin SI: Factor VIII: structure and function in blood clotting. Am J Hematol. 1984 Apr;16(3):297-306. [PubMed:6424437]
  2. Wynn TT, Gumuscu B: Potential role of a new PEGylated recombinant factor VIII for hemophilia A. J Blood Med. 2016 Jun 20;7:121-8. doi: 10.2147/JBM.S82457. eCollection 2016. [PubMed:27382347]
  3. Adynovate FDA label [File]

Drug created on November 18, 2015 09:20 / Updated on November 16, 2018 11:27