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, is a recombinant full-length human coagulation factor VIII (2,332 amino acids with a molecular weight (MW) of 280 kDa) covalently conjugated with at least one molecule of polyethylene glycol (MW 20 kDa). The therapeutic activity of Antihemophilic Factor (Recombinant), PEGylated is a derivative of its parent drug, Antihemophilic Factor (Recombinant). Antihemophilic Factor (Recombinant) is purified from the culture medium using several chromatography columns. The purification process includes immunoaffinity chromatography, in which a monoclonal antibody directed against factor VIII is promoted to selectively isolate the factor VIII from the medium. The production process includes a viral inactivation solvent-detergent treatment step. The Antihemophilic Factor (Recombinant) molecule is then covalently conjugated with the polyethylene glycol, which primarily targets lysine residues [Label].

Antihemophilic Factor (Recombinant), PEGylated, was approved by the FDA in November 2015 as the product Adynovate [Label].

PEGylation is the covalent attachment of a polyethylene glycol polymer, called PEG, to a drug or protein. It is believed that PEGylation reduces the binding of ADYNOVATE to the LRP1 clearance receptor, allowing for an increased duration of drug circulation in the plasma [6].

Protein chemical formula
Not Available
Protein average weight
Not Available
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
International/Other Brands
Advate (Baxter)
Categories
UNII
Not Available
CAS number
1628187-15-4

Pharmacology

Indication

For the treatment of hemophilia A (congenital factor VIII deficiency) [Label]. 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

Hemophilia A patients have a deficiency of factor VIII, resulting in a prolonged, patient plasma clotting time as indicated 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 profuse bleeding into the joints, muscles or internal organs, spontaneously/as a result of trauma [17]. The administration of this drug increases plasma concentrations of factor VIII and serves to temporarily correct the coagulation disorder in hemophilia A patients [Label].

One study found that BAX 855, a pegylated full-length recombinant factor VIII with extended half-life, was very effective in the prevention and treatment of bleeding episodes [12].

Mechanism of action

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

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 changes the surface charge of the protein that inhibits receptor-mediated clearance [4]. Specifically, the protein is known as Low-density lipoprotein receptor-related protein (LRP) [5].

The plasma levels of Factor VIII are increased with replacement therapy, which enables a temporary correction of the factor deficiency, thus a correction of the bleeding tendency [17].

TargetActionsOrganism
Uvon Willebrand factorNot AvailableHuman
UCoagulation factor IXNot AvailableHuman
UCoagulation factor XNot AvailableHuman
Absorption
Not Available
Volume of distribution

Steady-state volume of distribution: 151 (mL kg− 1) (rat) [13]

Apparent volume of distribution: 204 (mL kg− 1) (rat) [13]

Vss: Children <6 years: 0.97 ± 0.23 dL/kg; Children 6 to <12 years: 1.59 ± 0.34 dL/kg [14]

Vss: Children and Adolescents 12 to <18 years: 0.56 ± 0.18 dL/kg; Adults ≥18 years: 0.43 ± 0.11 dL/kg [14]

I-octocog alfa (Recombinant pegylated Factor VIII formulation) was distributed mostly into organs and highly vascularized tissues. The thyroid gland showed the highest concentrations of 125I -Recombinant. The highest octocog-alfa concentrations were discovered in the following organs (in descending order of concentrations): the spleen, stomach, liver, lung, kidney, and cardiovascular tissue. A negligible amount was detected in the skeletal muscle and brain. 60 seconds after the infusion, 65% of total infused 125I –octocog alfa (dpm/ml) was present in the blood [L15640].

Protein binding
Not Available
Metabolism

Octocog alfa (also known as pegylated factor VIII, recombinant) is catabolized by protease enzymes in both the plasma and liver. 8 hours after the drug administration, about 1/3 of metabolites were found in the plasma. 24 hours after the infusion of Advate, significant distribution was observed only in the thyroid [15].

The relative distribution of the metabolites of radioactive labeled octocog alfa excreted in the urine, bile and faeces was studied in rats. Octocog alfa was primarily excreted in the urine. During the first 48 hours after administration, approximately 63%, 23% and 1% of the total radioactivity was recovered in the urine, bile and faeces, respectively. By 72h after injection, approximately 83% and 7% of the administered radioactivity was recovered in the urine and faeces, respectively. The amount of animal pharmacokinetic investigations as well as the choice of methods is considered appropriate since factor VIII is an endogenous human protein with a relatively simple metabolic pathway [3, 15, 14, 11].

Route of elimination

Excretion: The relative distribution of the metabolites of 125I -radiolabelled octocog alfa excreted in the urine, bile and faeces was studied in rats. Octocog alfa was primarily excreted in the urine. During the first 48 hours after administration, approximately 63%, 23% and 1% of the total radioactivity was found in the urine, bile and faeces, respectively. By 72 hours after administration, approximately 83% and 7% of the administered radioactivity was recovered in the urine and faeces, respectively [15].

Half life

This drug exhibits an extended terminal half-life through pegylation of the parent molecule, which reduces binding to the physiological factor VIII clearance receptor (LRP1) [Label].

The clearance was 1.79 mL(-1) h(-1) kg(-1). The mean terminal half-life of N8-GP was 19.0 h (range: 11.6-27.3 h), 1.6-fold longer than that of the patients' previous products. CONCLUSIONS:

Children <6 years: 11.8 ± 2.43 hours; Children 6 to <12 years: 12.4 ± 1.67 hours; Children and Adolescents 12 to <18 years: 13.43 ± 4.05 hours; Adults ≥18 years: 14.69 ± 3.79 hours [14]

The average half-life (T1/2) of FVIII products is in the range of 10 to 14 hours. This requires administration of Factor VIII every other day, or every 2 to 3 days when based on each patient’s individual pharmacokinetic (PK) profile [3].

The pharmacokinetic studies of PEG-FVIII conducted in hemophilic mouse models demonstrated that the half-life of PEGylated factor is more than doubled (4.9 hours) when compared to non-PEGylated full-length recombinant FVIII (1.9 hours) [2].

Clearance

Higher clearance, a shorter half-life and lower recovery of factor VIII has been observed in children less than 12 years old. Dose adjustment and/or frequent dosing based on per kg body weight may be needed in this population [Label].

Toxicity

The serious adverse reactions seen with ADVATE are hypersensitivity reactions and the development of high-titer inhibitors necessitating alternative treatments to factor VIII.

The most common adverse reactions observed in clinical trials (frequency ≥10% of subjects) were pyrexia, headache, cough, nasopharyngitis, vomiting, arthralgia, and limb injury [Label].

Serious adverse events with Advate(®) therapy include the development of high-titer factor VIII inhibitors (usually in previously untreated patients) and hypersensitivity reactions [Label].

There were no animal studies for carcinogenicity, in vivo mutagenicity, fertility, reproductive toxicity or teratogenicity conducted with PEG-FVIII. As PEG-FVIII is a recombinant, human protein, animals receiving repeated doses of the product developed antibodies against FVIII that both accelerated clearance of the protein and in some cases, neutralized its pro-coagulant activity. Therefore, long-term, repeat-dose toxicity studies as well as the standard carcinogenicity bioassay (i.e., 2 years of daily PEG-FVIII dosing in both rats and mice) were not feasible to conduct.

Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
AcetaminophenAcetaminophen may decrease the excretion rate of Antihemophilic Factor (Recombinant), PEGylated which could result in a higher serum level.
Acetylsalicylic acidAcetylsalicylic acid may decrease the excretion rate of Antihemophilic Factor (Recombinant), PEGylated which could result in a higher serum level.
AlprazolamAlprazolam may decrease the excretion rate of Antihemophilic Factor (Recombinant), PEGylated which could result in a higher serum level.
AmilorideAmiloride may increase the excretion rate of Antihemophilic Factor (Recombinant), PEGylated which could result in a lower serum level and potentially a reduction in efficacy.
AmitriptylineAntihemophilic Factor (Recombinant), PEGylated may decrease the excretion rate of Amitriptyline which could result in a higher serum level.
AmlodipineAmlodipine may decrease the excretion rate of Antihemophilic Factor (Recombinant), PEGylated which could result in a higher serum level.
AmoxicillinAmoxicillin may decrease the excretion rate of Antihemophilic Factor (Recombinant), PEGylated which could result in a higher serum level.
AmphetamineAmphetamine may decrease the excretion rate of Antihemophilic Factor (Recombinant), PEGylated which could result in a higher serum level.
AmpicillinAmpicillin may decrease the excretion rate of Antihemophilic Factor (Recombinant), PEGylated which could result in a higher serum level.
AnagrelideThe therapeutic efficacy of Antihemophilic Factor (Recombinant), PEGylated can be decreased when used in combination with Anagrelide.
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. Adynovate Pro [Link]
  7. Adynovate assessment report EMA [Link]
  8. Safety and prolonged activity of recombinant factor VIII Fc fusion protein in hemophilia A patients [Link]
  9. Potential role of a new PEGylated recombinant factor VIII for hemophilia A [Link]
  10. Potential role of a new PEGylated recombinant factor VIII for hemophilia A [Link]
  11. PEGylation of a Factor VIII–Phosphatidylinositol Complex: Pharmacokinetics and Immunogenicity in Hemophilia A Mice [Link]
  12. Pegylated, full-length, recombinant factor VIII for prophylactic and on-demand treatment of severe hemophilia A [Link]
  13. Non-clinical pharmacokinetics and pharmacodynamics of rVIII-SingleChain, a novel recombinant single-chain factor VIII [Link]
  14. Antihemophilic Factor (Recombinant [Pegylated]) [Link]
  15. EMA label Adate [Link]
  16. F8 gene coagulation factor VIII [Link]
  17. 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
1Active Not RecruitingBasic 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
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. F8 gene coagulation factor VIII [Link]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Serine-type endopeptidase activity
Specific Function
Factor IX is a vitamin K-dependent plasma protein that participates in the intrinsic pathway of blood coagulation by converting factor X to its active form in the presence of Ca(2+) ions, phospholi...
Gene Name
F9
Uniprot ID
P00740
Uniprot Name
Coagulation factor IX
Molecular Weight
51778.11 Da
References
  1. F8 gene coagulation factor VIII [Link]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Serine-type endopeptidase activity
Specific Function
Factor Xa is a vitamin K-dependent glycoprotein that converts prothrombin to thrombin in the presence of factor Va, calcium and phospholipid during blood clotting.
Gene Name
F10
Uniprot ID
P00742
Uniprot Name
Coagulation factor X
Molecular Weight
54731.255 Da
References
  1. F8 gene coagulation factor VIII [Link]

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]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Phosphatidylcholine transporter activity
Specific Function
Catalyzes the transfer of phosphatidylcholine between membranes. Binds a single lipid molecule.
Gene Name
PCTP
Uniprot ID
Q9UKL6
Uniprot Name
Phosphatidylcholine transfer protein
Molecular Weight
24843.145 Da

Drug created on November 18, 2015 09:20 / Updated on September 18, 2018 23:02