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| Primary information |
|---|
| ID | 10884 |
| Therapeutic ID | Th1240 |
| Protein Name | Erythropoietin |
| Sequence | >Th1240_Erythropoietin
APPRLICDSRVLERYLLEAKEAENITTGCAEHCSLNENITVPDTKVNFYAWKRMEVGQQAVEVWQGLALLSEAVLRGQALLVNSSQPWEPLQLHVDKAVSGLRSLTTLLRALGAQKEAISPPDAASAAPLRTITADTFRKLFRVYSNFLRGKLKLYTGEACRTGDR
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| Molecular Weight | 18396.1 |
| Chemical Formula | C815H1317N233O241S5 |
| Isoelectric Point | 8.75 |
| Hydrophobicity | NA |
| Melting point | 53 °C |
| Half-life | **Healthy volunteers:** The half life is approximately 4 hours in healthy volunteers receiving an intravenous injection [F85]. A half-life of approximately 6 hours has been reported in children [F85]., **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 [FDA Label]. , **Cancer patients receiving cyclic chemotherapy:** Following subcutaneous administration, the average half life is 40 hours with range of 16 to 67 hours [FDA Label]. |
| 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 [FDA 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 [FDA 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 [L2784]. 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 [A7504]. Epoetin alfa formulations can be administered intravenously or subcutaneously. |
| Indication/Disease | 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. |
| 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 [F85]. 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 [F85]. 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 [FDA Label]. Epoetin alfa was shown to be effective in increasing hematocrit in zidovudine-treated HIV-infected patients and anemic cancer patients undergoing chemotherapy [FDA Label]. |
| Mechanism of Action | Erythropoietin or exogenous epoetin alfa binds to the erythropoietin receptor (EPO-R) and activates intracellular signal transduction pathways [A33079]. The affinity (Kd) of EPO for its receptor on human cells is ~100 to 200 pM [A33080]. 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 [A33079]. 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 [A33079]. 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-1 [A33079]. |
| 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 [FDA Label]. |
| 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 [A33080]. |
| 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) [A33080, L85]. The bioavailability of subcutaneous injectable erythropoietin is much lower than that of the intravenously administered product and is approximately 20-40% [A33080, L85]. **Adult and paediatric patients with CRF:** Following subcutaneous administration, the peak plasma levels are achieved within 5 to 24 hours [FDA 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 [FDA Label]. |
| 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 [A33080, A33076]. |
| Clearance | **Healthy volunteers: ** In male volunteers receiving intravenous epoetin alfa, the total body clearance was approximately 8.12 ± 1.00 mL/h/kg [A33076]. **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 [FDA Label]. The patients receiving a 40,000 Units SC weekly dosing regimen display a lower clearance (9.2 ± 4.7 mL/h/kg) [FDA Label]. |
| Categories | Blood and Blood Forming Organs |
| Patents Number | NA |
| Date of Issue | NA |
| Date of Expiry | NA |
| Drug Interaction | NA |
| Target | Erythropoietin receptor |
| Brand Name | Abseamed |
| Company | Medice Arzneimittel Pütter Gmb H Co. Kg |
| Brand Description | Medice Arzneimittel Pütter Gmb H Co. Kg |
| Prescribed For | Intravenous; Subcutaneous |
| Chemical Name | 4000 IU/0.4ml |
| Formulation | NA |
| Physical Appearance | The most common side effects with Abseamed (which may affect more than 1 in 10 people) are nausea (feeling sick), diarrhoea, vomiting, fever and headache. Flu-like illness may occur especially at the start of treatment. |
| Route of Administration | Abseamed contains the active substance epoetin alfa and is a ‘biosimilar medicine’. This means that Abseamed is highly similar to another biological medicine (the ‘reference medicine’) that is already authorised in the EU. The reference medicine for Abseamed is Eprex/Erypo. |
| Recommended Dosage | to treat anaemia (low red blood cell counts) that is causing symptoms in patients with chronic kidney failure (long-term, progressive decrease in the ability of the kidneys to work properly) or other kidney problems; to treat anaemia in adults receiving chemotherapy for certain types of cancer and to reduce the need for blood transfusions; to increase the amount of blood that can be taken in adult patients with moderate anaemia and normal blood iron levels who are going to have an operation and donate their own blood before surgery (autologous blood transfusion); to reduce the need for blood transfusions in adults with moderate anaemia who are about to undergo major orthopaedic (bone) surgery, such as hip surgery. It is used in patients with normal blood iron levels who could experience complications from a blood transfusion, if they do not donate their own blood before surgery and are expected to lose 900 to 1,800 ml of blood; to treat anaemia in adults with myelodysplastic syndromes (conditions in which the production of healthy blood cells is defective). Abseamed is used when patients are at low or intermediate risk of developing acute myeloid leukaemia and have low levels of the natural hormone erythropoietin. |
| Contraindication | potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,3-triaza-4-azanidacyclopenta-2,5-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol |
| Side Effects | NA |
| Useful Link 1 | Link |
| Useful Link 2 | Link |
| Remarks | NA |