Aflibercept

Identification

Summary

Aflibercept is a vascular endothelial growth factor (VEGF) inhibitor used to treat Neovascular (Wet) Age-Related Macular Degeneration (AMD), various types of macular edema and diabetic retinopathy.

Brand Names
Eylea, Zaltrap
Generic Name
Aflibercept
DrugBank Accession Number
DB08885
Background

Aflibercept is a recombinant protein composed of the binding domains of two human vascular endothelial growth factor (VEGF) receptors fused with the Fc region of human immunoglobulin gamma 1 (IgG1). Structurally, Aflibercept is a dimeric glycoprotein with a protein molecular weight of 96.9 kilo Daltons (kDa). It contains approximately 15% glycosylation to give a total molecular weight of 115 kDa. All five putative N-glycosylation sites on each polypeptide chain predicted by the primary sequence can be occupied with carbohydrate and exhibit some degree of chain heterogeneity, including heterogeneity in terminal sialic acid residues, except at the single unsialylated site associated with the Fc domain. Aflibercept, as an ophthalmic agent, is used in the treatment of macular edema following Central Retinal Vein Occlusion (CRVO) and neovascular Age-Related Macular Degeneration (AMD). Ziv-aflibercept, under the brand name Zaltrap, was developed as an injection for treatment of metastatic colorectal cancer. FDA approved in November 18, 2011 and EMA approved in November 2012.

Type
Biotech
Groups
Approved
Biologic Classification
Protein Based Therapies
Fusion proteins
Protein Chemical Formula
C4318H6788N1164O1304S32
Protein Average Weight
115000.0 Da (with glycosylation)
Sequences
> Protein sequence for aflibercept
SDTGRPFVEMYSEIPEIIHMTEGRELVIPCRVTSPNITVTLKKFPLDTLIPDGKRIIWDS
RKGFIISNATYKEIGLLTCEATVNGHLYKTNYLTHRQTNTIIDVVLSPSHGIELSVGEKL
VLNCTARTELNVGIDFNWEYPSSKHQHKKLVNRDLKTQSGSEMKKFLSTLTIDGVTRSDQ
GLYTCAASSGLMTKKNSTFVRVHEKDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISR
TPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLN
GKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPS
DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNH
YTQKSLSLSPG
Download FASTA Format
Synonyms
  • Aflibercept
  • Aflibercept (genetical recombination)
  • Ziv-aflibercept
External IDs
  • AVE 0005
  • AVE 005
  • AVE-0005
  • AVE0005
  • Bay 86-5321
  • BAY-865321
  • Bay86-5321

Pharmacology

Indication

The opthalmic agent is used for the treatment of neovascular (wet) age-related mascular degeneration (AMD) and macular edema following central retinal vein occulsion (CRVO). The systemic injection, known as ziv-aflibercept, in combination with 5-fluorouracil, leucovorin, irinotecan-(FOLFIRI), is for the treatment of metastatic colorectal cancer that is resistant to or progressed following treatment with oxaliplatin.

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

Compared to other anti-VEGF drugs like bevacizumab and ranibizumab, aflibercept has a higher binding affinity to VEGF-A (Kd = 0.5 pM).

Mechanism of action

Ablibercept is a recombinant fusion protein that acts as a decoy receptor for the ligands, vascular endothelial growth factor-A (VEGF-A) and placental growth factor (PIGF). It prevents these ligands to binding to endothelial receptors, VEGFR-1 and VEGFR-2, to suppress neovascularization and decrease vascular permeability. This ultimately will slow vision loss or the progression of metastatic colorectal cancer.

TargetActionsOrganism
AVascular endothelial growth factor A
binder
Humans
APlacenta growth factor
binder
Humans
AVascular endothelial growth factor B
binder
Humans
Absorption

In patients with wet AMD and CRVO, the mean peak plasma concentration (Cmax) was 0.02 mcg/mL and 0.05 mcg/mL respectively. These concentrations were reached in 1 to 3 days. Aflibercept did not accumulate when administered as repeated doses intravitreally every 4 weeks.

Volume of distribution

After intravenous injection of aflibercept, the volume of distribution is 6 L.

Protein binding

Not Available

Metabolism

Because aflibercept is a protein, it is expected to be broken down via proteolysis into smaller peptides and amino acids. The cytochrome P450 enzyme system is not involved in the metabolism of aflibercept.

Route of elimination

Via kidney and liver

Half-life

Intravitreal half-life= 7.13 days in humans; Terminal elimination half-life of free aflibercept in plasma was 5 to 6 days after IV injection of 2 - 4 mg/kg dose.

Clearance

When cancer patients were given 2-9 mg/kg every 2 or 3 week; 1 hour IV infusion of aflibercept the typical estimated clearances were as follows: CL of free aflibercept (CLf) = 0.88 L/day; CL of bound aflibercept (CLf) = 0.19 L/day; Patients clear free aflibercept faster if they had low albumin or high alkaline phosphatase levels.

Adverse Effects
Adverseeffects
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Toxicity

For all intravitreal VEGF inhibitors, there is increased risk of stroke and myocardial infarction. An increase in intraocular pressure may also occur. When used intravenously, most common adverse reactions were leukopenia, diarrhea, neutropenia, proteinuria, AST increased, stomatitis, fatigue, thrombocytopenia, ALT increased, hypertension, weight decreased, decreased appetite, epistaxis, abdominal pain, dysphonia, serum creatinine increased, and headache.

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.
Not Available
Food Interactions
No interactions found.

Products

Products2
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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
EyleaInjection, solution40 mg/mlIntravitrealBayer Ag2016-09-08Not applicableEU flag
EyleaSolution40 mg / mLIntravitrealBayer2020-11-17Not applicableCanada flag
EyleaInjection, solution40 mg/1mLIntravitrealRegeneron Pharmaceuticals, Inc.2011-11-21Not applicableUS flag
EyleaSolution40 mg / mLIntravitrealBayer2013-12-23Not applicableCanada flag
EyleaInjection, solution40 mg/mlIntravitrealBayer Ag2016-09-08Not applicableEU flag
ZaltrapInjection, solution, concentrate25 mg/mlIntravenousSanofi Aventis Groupe2016-09-08Not applicableEU flag
ZaltrapInjection, solution, concentrate25 mg/mlIntravenousSanofi Aventis Groupe2016-09-08Not applicableEU flag
ZaltrapSolution, concentrate200 mg/8mLIntravenoussanofi-aventis U.S. LLC2012-08-03Not applicableUS flag
ZaltrapSolution200 mg / 8 mLIntravenousSanofi Aventis2014-05-082020-07-13Canada flag
ZaltrapInjection, solution, concentrate25 mg/mlIntravenousSanofi Aventis Groupe2016-09-08Not applicableEU flag

Categories

ATC Codes
S01LA05 — AfliberceptL01XX44 — Aflibercept
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
15C2VL427D
CAS number
862111-32-8

References

General References
  1. Freund KB, Mrejen S, Gallego-Pinazo R: An update on the pharmacotherapy of neovascular age-related macular degeneration. Expert Opin Pharmacother. 2013 Jun;14(8):1017-28. doi: 10.1517/14656566.2013.787410. Epub 2013 Apr 8. [Article]
  2. Thai HT, Veyrat-Follet C, Mentre F, Comets E: Population pharmacokinetic analysis of free and bound aflibercept in patients with advanced solid tumors. Cancer Chemother Pharmacol. 2013 Jul;72(1):167-80. doi: 10.1007/s00280-013-2182-1. Epub 2013 May 15. [Article]
KEGG Drug
D09574
PubChem Substance
347910379
RxNav
1232150
ChEMBL
CHEMBL1742982
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Aflibercept
FDA label
Download (325 KB)
MSDS
Download (91.1 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4Active Not RecruitingTreatmentDiabetic Macular Edema (DME)2
4Active Not RecruitingTreatmentDiabetic Retinopathy (DR)1
4CompletedBasic ScienceNeovascular Age-Related Macular Degeneration (nAMD)1
4CompletedOtherWet Macular Degeneration1
4CompletedPreventionDiabetic Macular Edema (DME)1
4CompletedTreatmentAge - Related Macular Degeneration (AMD)5
4CompletedTreatmentAge - Related Macular Degeneration (AMD) / Polypoidal Choroidal Vasculopathy (PCV)1
4CompletedTreatmentAMD (With Persistent or Recurrent Fluid Despite Monthly Intravitreal Anti-VEGF Therapy)1
4CompletedTreatmentAnti Vascular Endothelial Growth Factor / Macular Degeneration1
4CompletedTreatmentBranch Retinal Vein Occlusion / Central Retinal Vein Occlusion (CRVO) / Diabetic Macular Edema (DME) / Retinal Vein Occlusion1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
InjectionIntravitreal
Injection, solutionIntravitreal40 mg/1mL
Injection, solutionIntravitreal40 MG/ML
SolutionIntravitreal40 mg / mL
Injection, solutionIntravitreal
SolutionIntraocular2 mg
InjectionIntravenous
Injection, solution, concentrateIntravenous25 mg/1ml
Injection, solution, concentrateIntravenous25 mg/ml
Injection, solution, concentrateIntravenous; Parenteral25 MG/ML
SolutionIntravenous100 mg / 4 mL
SolutionIntravenous200 mg / 8 mL
Solution, concentrateIntravenous100 mg/4mL
Solution, concentrateIntravenous200 mg/8mL
InjectionParenteral
Injection, solution, concentrateIntravenous
SolutionOphthalmic40 mg/1ml
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US7306799No2007-12-112020-05-23US flag
US7531173No2009-05-122026-02-02US flag
US7374758No2008-05-202020-05-23US flag
US7608261No2009-10-272027-06-14US flag
US7070959No2006-07-042020-05-23US flag
US7374757No2008-05-202020-05-23US flag

Properties

State
Liquid
Experimental Properties
PropertyValueSource
water solubility>100 mg/mLMSDS

Targets

Drugtargets2
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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Binder
General Function
Vascular endothelial growth factor receptor binding
Specific Function
Growth factor active in angiogenesis, vasculogenesis and endothelial cell growth. Induces endothelial cell proliferation, promotes cell migration, inhibits apoptosis and induces permeabilization of...
Gene Name
VEGFA
Uniprot ID
P15692
Uniprot Name
Vascular endothelial growth factor A
Molecular Weight
27042.205 Da
References
  1. Browning DJ, Kaiser PK, Rosenfeld PJ, Stewart MW: Aflibercept for age-related macular degeneration: a game-changer or quiet addition? Am J Ophthalmol. 2012 Aug;154(2):222-6. doi: 10.1016/j.ajo.2012.04.020. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Binder
General Function
Heparin binding
Specific Function
Growth factor active in angiogenesis and endothelial cell growth, stimulating their proliferation and migration. It binds to the receptor FLT1/VEGFR-1. Isoform PlGF-2 binds NRP1/neuropilin-1 and NR...
Gene Name
PGF
Uniprot ID
P49763
Uniprot Name
Placenta growth factor
Molecular Weight
24788.45 Da
References
  1. Browning DJ, Kaiser PK, Rosenfeld PJ, Stewart MW: Aflibercept for age-related macular degeneration: a game-changer or quiet addition? Am J Ophthalmol. 2012 Aug;154(2):222-6. doi: 10.1016/j.ajo.2012.04.020. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Binder
General Function
Vascular endothelial growth factor receptor 1 binding
Specific Function
Growth factor for endothelial cells. VEGF-B167 binds heparin and neuropilin-1 whereas the binding to neuropilin-1 of VEGF-B186 is regulated by proteolysis.
Gene Name
VEGFB
Uniprot ID
P49765
Uniprot Name
Vascular endothelial growth factor B
Molecular Weight
21601.56 Da
References
  1. Browning DJ, Kaiser PK, Rosenfeld PJ, Stewart MW: Aflibercept for age-related macular degeneration: a game-changer or quiet addition? Am J Ophthalmol. 2012 Aug;154(2):222-6. doi: 10.1016/j.ajo.2012.04.020. [Article]

Drug created on May 24, 2013 21:16 / Updated on September 28, 2021 07:54