Erythropoietin

Identification

Name
Erythropoietin
Accession Number
DB00016
Description

Erythropoietin (EPO) is a growth factor produced in the kidneys that stimulates the production of red blood cells. It works by promoting the division and differentiation of committed erythroid progenitors in the bone marrow Label. Epoetin alfa (Epoge) was developed by Amgen Inc. in 1983 as the first rhEPO commercialized in the United States, followed by other alfa and beta formulations. Epoetin alfa is a 165-amino acid erythropoiesis-stimulating glycoprotein produced in cell culture using recombinant DNA technology and is used for the treatment of patients with anemia associated with various clinical conditions, such as chronic renal failure, antiviral drug therapy, chemotherapy, or a high risk for perioperative blood loss from surgical procedures Label. It has a molecular weight of approximately 30,400 daltons and is produced by mammalian cells into which the human erythropoietin gene has been introduced. The product contains the identical amino acid sequence of isolated natural erythropoietin and has the same biological activity as the endogenous erythropoietin. Epoetin alfa biosimilar, such as Retacrit (epoetin alfa-epbx or epoetin zeta), has been formulated to allow more access to treatment options for patients in the market 5. The biosimilar is approved by the FDA and EMA as a safe, effective and affordable biological product and displays equivalent clinical efficacy, potency, and purity to the reference product 1. Epoetin alfa formulations can be administered intravenously or subcutaneously.

Type
Biotech
Groups
Approved
Biologic Classification
Protein Based Therapies
Hormones
Protein Structure
Db00016
Protein Chemical Formula
C815H1317N233O241S5
Protein Average Weight
18396.1 Da
Sequences
>DB00016 (Erythropoietin) sequence
APPRLICDSRVLERYLLEAKEAENITTGCAEHCSLNENITVPDTKVNFYAWKRMEVGQQA
VEVWQGLALLSEAVLRGQALLVNSSQPWEPLQLHVDKAVSGLRSLTTLLRALGAQKEAIS
PPDAASAAPLRTITADTFRKLFRVYSNFLRGKLKLYTGEACRTGDR
Download FASTA Format
Synonyms
  • E.P.O.
  • Epoetin alfa
  • Epoetin alfa rDNA
  • Epoetin alfa-epbx
  • Epoetin alfa, recombinant
  • Epoetin beta
  • Epoetin beta rDNA
  • Epoetin epsilon
  • Epoetin gamma
  • Epoetin gamma rDNA
  • Epoetin kappa
  • Epoetin omega
  • Epoetin theta
  • Epoetin zeta
  • Epoetina alfa
  • Epoetina beta
  • Epoetina dseta
  • Epoetina zeta
  • Epoétine zêta
  • Epoetinum zeta
  • Erythropoiesis stimulating factor
  • Erythropoietin (human, recombinant)
  • Erythropoietin (recombinant human)
  • ESF
  • SH-polypeptide-72
External IDs
  • BM 06.019

Pharmacology

Pharmacology
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Indication

Indicated in adult and paediatric patients for the:

  • treatment of anemia due to Chronic Kidney Disease (CKD) in patients on dialysis and not on dialysis.
  • treatment of anemia due to zidovudine in patients with HIV-infection.
  • treatment of anemia due to the effects of concomitant myelosuppressive chemotherapy, and upon initiation, there is a minimum of two additional months of planned chemotherapy.
  • reduction of allogeneic RBC transfusions in patients undergoing elective, noncardiac, nonvascular surgery.
Associated Conditions
Associated Therapies
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

Erythropoietin and epoetin alfa are involved in the regulation of erythrocyte differentiation and the maintenance of a physiological level of circulating erythrocyte mass. It is reported to increase the reticulocyte count within 10 days of initiation, followed by increases in the RBC count, hemoglobin, and hematocrit, usually within 2 to 6 weeks 6. Depending on the dose administered, the rate of hemoglobin increase may vary. In patients receiving hemodialysis, a greater biologic response is not observed at doses exceeding 300 Units/kg 3 times weekly 6.

Epoetin alfa serves to restore erythropoietin deficiency in pathological and other clinical conditions where normal production of erythropoietin is impaired or compromised. In anemic patients with chronic renal failure (CRF), administration with epoetin alfa stimulated erythropoiesis by increasing the reticulocyte count within 10 days, followed by increases in the red cell count, hemoglobin, and hematocrit, usually within 2 to 6 weeks Label. Epoetin alfa was shown to be effective in increasing hematocrit in zidovudine-treated HIV-infected patients and anemic cancer patients undergoing chemotherapy Label.

Mechanism of action

Erythropoietin or exogenous epoetin alfa binds to the erythropoietin receptor (EPO-R) and activates intracellular signal transduction pathways 3. The affinity (Kd) of EPO for its receptor on human cells is ∼100 to 200 pM 4. Upon binding to EPO-R on the surface of erythroid progenitor cells, a conformational change is induced which brings EPO-R-associated Janus family tyrosine protein kinase 2 (JAK2) molecules into close proximity. JAK2 molecules are subsequently activated via phosphorylation, then phosphorylate tyrosine residues in the cytoplasmic domain of the EPO-R that serve as docking sites for Src homology 2-domain-containing intracellular signaling proteins 3. The signalling proteins include STAT5 that once phosphorylated by JAK2, dissociates from the EPO-R, dimerizes, and translocates to the nucleus where they serve as transcription factors to activate target genes involved in cell division or differentiation, including the apoptosis inhibitor Bcl-x 3. The inhibition of apoptosis by the EPO-activated JAK2/STAT5/Bcl-x pathway is critical in erythroid differentiation. Via JAK2-mediated tyrosine phosphorylation, erythropoietin and epoetin alfa also activates other intracellular proteins involved in erythroid cell proliferation and survival, such as Shc , phosphatidylinositol 3-kinase (PI3K), and phospholipase C-γ1 3.

TargetActionsOrganism
AErythropoietin receptor
agonist
Humans
Absorption

The time to reach peak concentration is slower via the subcutaneous route than the intravenous route which ranges from 20 to 25 hours, and the peak is always well below the peak achieved using the intravenous route (5–10% of those seen with IV administration) 4. The bioavailability of subcutaneous injectable erythropoietin is much lower than that of the intravenously administered product and is approximately 20-40% 4.

Adult and paediatric patients with CRF: Following subcutaneous administration, the peak plasma levels are achieved within 5 to 24 hours Label.

Cancer patients receiving cyclic chemotherapy: The average time to reach peak plasma concentration was approximately 13.3 ± 12.4 hours after 150 Units/kg three times per week (TIW) subcutaneous (SC) dosing. The Cmax is expected be 3- to 7- fold higher and the Tmax is expected to be 2- to 3-fold longer in patients receiving a 40,000 Units SC weekly dosing regimen Label.

Volume of distribution

In healthy volunteers, the volume of distribution of intravenous epoetin alfa was generally similar to the plasma volume (range of 40–63.80 mL/kg), indicating limited extravascular distribution 4,2.

Protein binding

No information of serum protein binding available.

Metabolism

Binding of erythropoietin and epoetin alfa to EPO-R leads to cellular internalization, which involves the degradation of the ligand. Erythropoietin and epoetin alfa may also be degraded by the reticuloendothelial scavenging pathway or lymphatic system 4.

Route of elimination

Erythropoietin and epoetin alfa are cleared via uptake and degradation via the EPO-R-expressing cells, and may also involve other cellular pathways in the interstitium, probably via cells in the reticuloendothelial scavenging pathway or lymphatic system 4. Only a small amount of unchanged epoetin alfa is found in the urine 7.

Half-life

Healthy volunteers: The half life is approximately 4 hours in healthy volunteers receiving an intravenous injection 6. A half-life of approximately 6 hours has been reported in children 6.

Adult and paediatric patients with CRF: The elimination half life following intravenous administration ranges from 4 to 13 hours, which is about 20% longer in CRF patients than that in healthy subjects. The half life is reported to be similar between adult patients receiving or not receiving dialysis Label.

Cancer patients receiving cyclic chemotherapy: Following subcutaneous administration, the average half life is 40 hours with range of 16 to 67 hours Label.

Clearance

*Healthy volunteers: * In male volunteers receiving intravenous epoetin alfa, the total body clearance was approximately 8.12 ± 1.00 mL/h/kg 2.

Cancer patients receiving cyclic chemotherapy: The average clearance was approximately 20.2 ± 15.9 mL/h/kg after 150 Units/kg three times per week (TIW) subcutaneous (SC) dosing Label. The patients receiving a 40,000 Units SC weekly dosing regimen display a lower clearance (9.2 ± 4.7 mL/h/kg) Label.

Adverse Effects
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Toxicity

Overdose from epoetin alfa include signs and symptoms associated with an excessive and/or rapid increase in hemoglobin concentration, including cardiovascular events. Patients with suspected or known overdose should be monitored closely for cardiovascular events and hematologic abnormalities. Polycythemia should be managed acutely with phlebotomy, as clinically indicated. Following resolution of the overdose, reintroduction of epoetin alfa therapy should be accompanied by close monitoring for evidence of rapid increases in hemoglobin concentration (>1 gm/dL per 14 days). In patients with an excessive hematopoietic response, reduce the dose in accordance with the recommendations described in the drug label Label.

Affected organisms
  • Humans and other mammals
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
AbemaciclibThe risk or severity of Thrombosis can be increased when Erythropoietin is combined with Abemaciclib.
AbirateroneThe risk or severity of Thrombosis can be increased when Erythropoietin is combined with Abiraterone.
AfatinibThe risk or severity of Thrombosis can be increased when Erythropoietin is combined with Afatinib.
AldesleukinThe risk or severity of Thrombosis can be increased when Erythropoietin is combined with Aldesleukin.
AlectinibThe risk or severity of Thrombosis can be increased when Erythropoietin is combined with Alectinib.
AlemtuzumabThe risk or severity of Thrombosis can be increased when Erythropoietin is combined with Alemtuzumab.
AlitretinoinThe risk or severity of Thrombosis can be increased when Erythropoietin is combined with Alitretinoin.
AlpelisibThe risk or severity of Thrombosis can be increased when Erythropoietin is combined with Alpelisib.
AltretamineThe risk or severity of Thrombosis can be increased when Erythropoietin is combined with Altretamine.
AminoglutethimideThe risk or severity of Thrombosis can be increased when Erythropoietin is combined with Aminoglutethimide.
Interactions
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Food Interactions
  • Administer iron supplement. When initiating an erythropoiesis-stimulating agent, evaluate iron stores and start iron supplementation if indicated. Most patients with chronic kidney disease require iron supplementation while taking an erythropoiesis-stimulating agent.

Products

Products
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International/Other Brands
Epobel (Nobel Ilac Pazarlama ve Sanayii Ltd. STI., Turkey) / Epocept (Lupin pharma) / Epofit (Intas pharma) / Epogin (Chugai) / Eqralys (Hemofarm AD) / Nanokine (Nanogen Pharmaceutical biotechnology, Vietnam))
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
AbseamedInjection, solution40000 IU/1.0mlIntravenous; SubcutaneousMedice Arzneimittel Pütter Gmb H Co. Kg2016-09-07Not applicableEU flag
AbseamedInjection, solution4000 IU/0.4mlIntravenous; SubcutaneousMedice Arzneimittel Pütter Gmb H Co. Kg2016-09-07Not applicableEU flag
AbseamedInjection, solution1000 IU/0.5mlIntravenous; SubcutaneousMedice Arzneimittel Pütter Gmb H Co. Kg2016-09-07Not applicableEU flag
AbseamedInjection, solution7000 IU/0.7mlIntravenous; SubcutaneousMedice Arzneimittel Pütter Gmb H Co. Kg2016-09-07Not applicableEU flag
AbseamedInjection, solution7000 IU/0.7mlIntravenous; SubcutaneousMedice Arzneimittel Pütter Gmb H Co. Kg2016-09-07Not applicableEU flag
AbseamedInjection, solution10000 IU/1.0mlIntravenous; SubcutaneousMedice Arzneimittel Pütter Gmb H Co. Kg2016-09-07Not applicableEU flag
AbseamedInjection, solution5000 IU/0.5mlIntravenous; SubcutaneousMedice Arzneimittel Pütter Gmb H Co. Kg2016-09-07Not applicableEU flag
AbseamedInjection, solution30000 IU/0.75mlIntravenous; SubcutaneousMedice Arzneimittel Pütter Gmb H Co. Kg2016-09-07Not applicableEU flag
AbseamedInjection, solution40000 IU/1mlIntravenous; SubcutaneousMedice Arzneimittel Pütter Gmb H Co. Kg2016-09-07Not applicableEU flag
AbseamedInjection, solution40000 IU/1.0mlIntravenous; SubcutaneousMedice Arzneimittel Pütter Gmb H Co. Kg2016-09-07Not applicableEU flag

Categories

ATC Codes
B03XA01 — Erythropoietin
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

Chemical Identifiers

UNII
64FS3BFH5W
CAS number
11096-26-7

References

General References
  1. Brinks V, Hawe A, Basmeleh AH, Joachin-Rodriguez L, Haselberg R, Somsen GW, Jiskoot W, Schellekens H: Quality of original and biosimilar epoetin products. Pharm Res. 2011 Feb;28(2):386-93. doi: 10.1007/s11095-010-0288-2. Epub 2010 Oct 1. [PubMed:20886265]
  2. Halstenson CE, Macres M, Katz SA, Schnieders JR, Watanabe M, Sobota JT, Abraham PA: Comparative pharmacokinetics and pharmacodynamics of epoetin alfa and epoetin beta. Clin Pharmacol Ther. 1991 Dec;50(6):702-12. [PubMed:1752115]
  3. Weiss MJ: New insights into erythropoietin and epoetin alfa: mechanisms of action, target tissues, and clinical applications. Oncologist. 2003;8 Suppl 3:18-29. [PubMed:14671225]
  4. Elliott S, Pham E, Macdougall IC: Erythropoietins: a common mechanism of action. Exp Hematol. 2008 Dec;36(12):1573-84. doi: 10.1016/j.exphem.2008.08.003. Epub 2008 Oct 14. [PubMed:18922615]
  5. FDA News Release: FDA approves first epoetin alfa biosimilar for the treatment of anemia [Link]
  6. EMA Summary of Product Characteristics: RETACRIT (epoetin alfa-epox) injection, for intravenous or subcutaneous use [File]
  7. Epoetin Alfa (Epogen®) Product Monograph [File]
UniProt
P01588
Genbank
X02158
PubChem Substance
46508122
RxNav
105694
ChEMBL
CHEMBL1201565
Therapeutic Targets Database
DAP000202
PharmGKB
PA10072
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Epoetin_alfa
AHFS Codes
  • 20:16.00 — Hematopoietic Agents
FDA label
Download (725 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedBasic ScienceHigh Blood Pressure (Hypertension) / Thrombotic events1
4CompletedBasic ScienceRenal Anemia1
4CompletedDiagnosticAnemia / Chronic Renal Failure (CRF)1
4CompletedPreventionDiabetic Nephropathy1
4CompletedPreventionDissection of Thoracic Aorta1
4CompletedPreventionOther and unspecified effects of high altitude1
4CompletedPreventionPatients Receiving a Kidney From a Non-Heart-Beating Donor1
4CompletedPreventionPremature Births1
4CompletedSupportive CareAnemia / Breast Cancer / Fatigue1
4CompletedSupportive CareAnemia / Cervical Cancers1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
  • Amgen Inc.
  • Centocor Ortho Biotech Inc.
  • DSM Corp.
  • Janssen-Ortho Inc.
  • JHP Pharmaceuticals LLC
  • Ortho-McNeil-Janssen Pharmaceuticals Inc.
  • Physicians Total Care Inc.
Dosage Forms
FormRouteStrength
Injection, solutionIntravenous; Subcutaneous1000 IU/0.5ml
Injection, solutionIntravenous; Subcutaneous10000 IU/1.0ml
Injection, solutionIntravenous; Subcutaneous2000 IU/1.0ml
Injection, solutionIntravenous; Subcutaneous20000 IU/0.5ml
Injection, solutionIntravenous; Subcutaneous3000 IU/0.3ml
Injection, solutionIntravenous; Subcutaneous30000 IU/0.75ml
Injection, solutionIntravenous; Subcutaneous4000 IU/0.4ml
Injection, solutionIntravenous; Subcutaneous40000 IU/1ml
Injection, solutionIntravenous; Subcutaneous40000 IU/1.0ml
Injection, solutionIntravenous; Subcutaneous5000 IU/0.5ml
Injection, solutionIntravenous; Subcutaneous6000 IU/0.6ml
Injection, solutionIntravenous; Subcutaneous7000 IU/0.7ml
Injection, solutionIntravenous; Subcutaneous8000 IU/0.8ml
Injection, solutionIntravenous; Subcutaneous9000 IU/0.9ml
SolutionIntravenous
Injection, solutionParenteral
Injection, solutionIntravenous
Injection, solutionIntravenous; Subcutaneous10000 IU/1ml
Injection, solutionSubcutaneous
SolutionIntravenous; Parenteral
Injection, solution
SolutionIntravenous; Subcutaneous10000 [iU]/1mL
SolutionIntravenous; Subcutaneous2000 [iU]/1mL
SolutionIntravenous; Subcutaneous20000 [iU]/1mL
SolutionIntravenous; Subcutaneous3000 [iU]/1mL
SolutionIntravenous; Subcutaneous4000 [iU]/1mL
SolutionIntravenous; Subcutaneous40000 1/1mL
Injection, solutionIntravenous; Subcutaneous2000 IU/0.5ml
Injection, solutionIntravenous; Subcutaneous20000 IU/1.0ml
Injection, solutionIntravenous; Subcutaneous3000 IU/0.5ml
Injection, solutionIntravenous; Subcutaneous30000 IU/1.0ml
Injection, solutionIntravenous; Subcutaneous4000 IU/0.5ml
Injection
Injection, solutionIntravenous; Subcutaneous
InjectionIntravenous; Subcutaneous
SolutionIntravenous; Subcutaneous
SolutionIntravenous; Subcutaneous2000 IU
Injection, powder, lyophilized, for solutionIntravenous; Subcutaneous
SolutionIntravenous; Subcutaneous4000 IU
SolutionParenteral
InjectionParenteral
InjectionIntravenous
Injection, powder, for solution
Injection, powder, for solution50000 IU
Injection, solution20000 IU
Injection, solution30000 IU
Injection, solution4000 IU
Injection, solution6000 IU
Injection, solutionIntravenous; Parenteral
Injection, solutionIntravenous; Parenteral; Subcutaneous
Injection, solutionIntravenous; Subcutaneous10000 IU
Injection, solutionIntravenous; Subcutaneous2000 IU
Injection, solutionIntravenous; Subcutaneous3000 IU
Injection, solutionIntravenous; Subcutaneous500 IU
Injection, solutionIntravenous; Subcutaneous5000 IU
Injection, solutionParenteral; Subcutaneous
PowderIntravenous
PowderParenteral
PowderSubcutaneous
Injection, solutionIntravenous; Subcutaneous30000 IU
Injection, solutionIntravenous; Subcutaneous10000 [iU]/1mL
Injection, solutionIntravenous; Subcutaneous2000 [iU]/1mL
Injection, solutionIntravenous; Subcutaneous20000 [iU]/1mL
Injection, solutionIntravenous; Subcutaneous3000 [iU]/1mL
Injection, solutionIntravenous; Subcutaneous4000 [iU]/1mL
Injection, solutionIntravenous; Subcutaneous40000 [iU]/1mL
Injection, solutionIntravenous; Subcutaneous1000 IU/0.3ml
Injection, solutionIntravenous; Subcutaneous2000 IU/0.6ml
Injection, solutionIntravenous; Subcutaneous3000 IU/0.9ml
Solution
Prices
Unit descriptionCostUnit
Epogen 40000 unit/ml Solution 1 Box Contains Ten 1ml Vials6852.3USD box
Epogen 20000 unit/ml Solution 1 Box Contains Ten 1ml Vials3157.44USD box
Epogen 10000 unit/ml Solution 1 Box Contains Ten 1ml Vials1578.72USD box
Procrit 40000 unit/ml vial767.03USD vial
Procrit 10000 unit/ml vial710.87USD vial
Epogen 40000 unit/ml vial640.37USD ml
Procrit 20000 unit/ml vial388.97USD ml
Procrit 20000 unit/ml Solution378.14USD ml
Procrit 10000 unit/ml Solution 2ml Vial358.02USD vial
Epogen 10000 unit/ml Solution 2ml Vial315.74USD vial
Epogen 20000 unit/ml vial303.6USD ml
Epogen 10000 unit/ml vial151.8USD ml
Procrit 4000 unit/ml vial74.17USD vial
Epogen 4000 unit/ml vial61.34USD vial
Procrit 3000 unit/ml vial55.63USD vial
Epogen 3000 unit/ml vial47.53USD vial
Procrit 2000 unit/ml vial37.09USD vial
Epogen 2000 unit/ml vial34.14USD vial
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
CA1339047No1997-05-272014-05-27Canada flag

Properties

State
Liquid
Experimental Properties
PropertyValueSource
melting point (°C)53 °CArakawa, T. et al., Biosci. Biotechnol. Biochem. 65:1321-1327 (2001)
isoelectric point8.75Not Available

Targets

Drugtargets
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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Agonist
General Function
Identical protein binding
Specific Function
Receptor for erythropoietin. Mediates erythropoietin-induced erythroblast proliferation and differentiation. Upon EPO stimulation, EPOR dimerizes triggering the JAK2/STAT5 signaling cascade. In som...
Gene Name
EPOR
Uniprot ID
P19235
Uniprot Name
Erythropoietin receptor
Molecular Weight
55064.725 Da
References
  1. LaMontagne KR, Butler J, Marshall DJ, Tullai J, Gechtman Z, Hall C, Meshaw A, Farrell FX: Recombinant epoetins do not stimulate tumor growth in erythropoietin receptor-positive breast carcinoma models. Mol Cancer Ther. 2006 Feb;5(2):347-55. [PubMed:16505108]
  2. Kokhaei P, Abdalla AO, Hansson L, Mikaelsson E, Kubbies M, Haselbeck A, Jernberg-Wiklund H, Mellstedt H, Osterborg A: Expression of erythropoietin receptor and in vitro functional effects of epoetins in B-cell malignancies. Clin Cancer Res. 2007 Jun 15;13(12):3536-44. [PubMed:17575216]
  3. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]

Drug created on June 13, 2005 13:24 / Updated on April 13, 2021 00:29