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Identification
NameAflibercept
Accession NumberDB08885
TypeBiotech
GroupsApproved
Description

Aflibercept is a recombinant fusion protein that comprises of two main components: the vascular endothelial growth factor (VEGF) binding portions from the extracellular domains of human VEGF receptors 1 and 2 which is then fused to the Fc portion of human 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.

Protein structureNo structure small
Related Articles
Protein chemical formulaC4318H6788N1164O1304S32
Protein average weight115000.0 Da (with glycosylation)
Sequences
> Protein sequence for aflibercept
SDTGRPFVEMYSEIPEIIHMTEGRELVIPCRVTSPNITVTLKKFPLDTLIPDGKRIIWDS
RKGFIISNATYKEIGLLTCEATVNGHLYKTNYLTHRQTNTIIDVVLSPSHGIELSVGEKL
VLNCTARTELNVGIDFNWEYPSSKHQHKKLVNRDLKTQSGSEMKKFLSTLTIDGVTRSDQ
GLYTCAASSGLMTKKNSTFVRVHEKDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISR
TPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLN
GKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPS
DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNH
YTQKSLSLSPG
Download FASTA Format
Synonyms
VEGF Trap
VEGF Trap-Eye
Ziv-Aflibercept
External Identifiers
  • AVE 0005
  • AVE 005
  • AVE-0005
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Eyleasolution40 mgintravitrealBayer Inc2013-12-23Not applicableCanada
Eyleainjection, solution40 mg/mLintravitrealRegeneron Pharmaceuticals, Inc.2011-11-21Not applicableUs
Zaltrapsolution, concentrate100 mg/4mLintravenousSanofi Aventis U.S. Llc2012-08-03Not applicableUs
Zaltrapsolution200 mgintravenousSanofi Aventis Canada Inc2014-05-08Not applicableCanada
Zaltrapsolution100 mgintravenousSanofi Aventis Canada Inc2014-05-08Not applicableCanada
Zaltrapsolution, concentrate200 mg/8mLintravenousSanofi Aventis U.S. Llc2012-08-03Not applicableUs
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International BrandsNot Available
Brand mixturesNot Available
SaltsNot Available
Categories
UNII15C2VL427D
CAS number862111-32-8
Taxonomy
DescriptionNot Available
KingdomOrganic Compounds
Super ClassOrganic Acids
ClassCarboxylic Acids and Derivatives
Sub ClassAmino Acids, Peptides, and Analogues
Direct ParentPeptides
Alternative ParentsNot Available
SubstituentsNot Available
Molecular FrameworkNot Available
External DescriptorsNot Available
Pharmacology
IndicationThe 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.
PharmacodynamicsCompared to other anti-VEGF drugs like bevacizumab and ranibizumab, aflibercept has a higher binding affinity to VEGF-A (Kd = 0.5 pM).
Mechanism of actionAblibercept 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.
Related Articles
AbsorptionIn 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 bindingNot 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 eliminationVia kidney and liver
Half lifeIntravitreal 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.

ToxicityFor 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.
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage forms
FormRouteStrength
Injection, solutionintravitreal40 mg/mL
Solutionintravitreal40 mg
Solutionintravenous100 mg
Solutionintravenous200 mg
Solution, concentrateintravenous100 mg/4mL
Solution, concentrateintravenous200 mg/8mL
PricesNot Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US7070959 No2006-07-042020-05-23Us
US7306799 No2005-03-252020-05-23Us
US7374757 No2008-05-202020-05-23Us
US7374758 No2008-05-202020-05-23Us
US7531173 No2009-05-122026-02-02Us
US7608261 No2009-10-272027-06-14Us
Properties
StateLiquid
Experimental Properties
PropertyValueSource
water solubility>100 mg/mLMSDS
References
Synthesis ReferenceNot Available
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. [PubMed:23560774 ]
  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. [PubMed:23673444 ]
External Links
ATC CodesL01XX44S01LA05
AHFS Codes
  • 10:00
  • 52:92
PDB EntriesNot Available
FDA labelDownload (325 KB)
MSDSDownload (91.1 KB)
Interactions
Drug InteractionsNot Available
Food InteractionsNot Available

Targets

Kind
Protein
Organism
Human
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 blood vessels. Binds to the FLT1/VEGFR1 and KDR/VEGFR2 receptors, heparan sulfate and heparin. NRP1/Neuropilin-1 binds isoforms VEGF-165 and VEGF-145. Isoform VEGF165B binds to KDR but does not activ...
Gene Name:
VEGFA
Uniprot ID:
P15692
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. [PubMed:22813448 ]
Kind
Protein
Organism
Human
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 NRP2/neuropilin-2 in a heparin-dependent manner. Also promotes cell tumor growth.
Gene Name:
PGF
Uniprot ID:
P49763
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. [PubMed:22813448 ]
Kind
Protein
Organism
Human
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
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. [PubMed:22813448 ]
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Drug created on May 24, 2013 15:16 / Updated on March 14, 2016 10:05