• Erythropoietin (EPO)

    Recombinant human erythropoietin (rHuEPO):

    Generic names: epoetin alfa, epoetin beta, epoetin delta, epoetin omega.
    Brand names: Epogen®, Procrit®, Eprex®, Recormon®, Dynepo®, Epomax®.


    Recombinant darbepoetin:
    Generic name: darbepoetin alfa.
    Brand name: Aranesp®.

    Class: Antianemic drugs; a potential alternative to blood transfusion.

    What is EPO?

    Erythropoietin (EPO) is a naturally occurring protein hormone produced by specialized cells in the kidneys. These cells are sensitive to the oxygen concentration in the blood, and increase the release of EPO when the oxygen concentration is low (hypoxia ).


    Figure 1 - Erythropoietin response to hypoxia

    Since oxygen is carried by red blood cells, too few red blood cells (anemia ) will result in erythropoietin release. EPO is a cytokine for stem cells in the bone marrow causing them to increase the production of erythrocytes (red blood cells). Recombinant erythropoietin is a therapeutic agent produced by DNA technology in mammalian cell culture.

    Recombinant human erythropoietin (rHuEPO)

    Since the 1980s a synthetic form of erythropoietin, produced by DNA technology has become available. It is virtually identical to the naturally occurring hormone. There are five erythropoiesis-stimulating agents currently available; epoetin-alpha, epoetin-beta, epoetin-omega, epoetin-delta, and darbepoetin-alpha. These agents all have the same amino-acid sequence, but glycolysation varies as a result of type- and host cell specific differences in the production process. Darbepoetin-alpha is an erythropoietin analogue, carrying two additional glycolysation sites, which produces a longer half-life and potency.

    Epoetin alfa


    EPO as a pharmaceutical

    In 1983, the gene coding for EPO was identified, leading to its synthesis as epoetin-alfa by American genetic research corporation, Amgen, who patented the drug under the name Epogen. In 1989, another company, Ortho Biotech, a subsidiary of Johnson and Johnson, began marketing the drug under license as Procrit in the US, and Eprex in the rest of the world.

    Recombinant DNA
    (rDNA) is an artificial DNA sequence resulting from the combining of two other DNA sequences in a plasmid.
    A recombinant protein is a protein produced by an organism after the relevant DNA is inserted into its genome (that is, by a genetically modified organism). This recombines the DNA of two different organisms.

    In the case of rHuEPO, the ovary cells of Chinese hamsters were transfected with the human gene for erythropoietin and epidermal growth factor receptor. The cells were then cultured in a serum-free medium, to which more growth factor was added to stimulate and accelerate the expression of human erythropoietin in large quantities. (See Growth and secretion of erythropoietin of Chinese hamster ovary cells )

    Epoetin-alfa is formulated as a colorless liquid in a solution of sodium chloride buffered with sodium citrate or sodium phosphate, and is packaged, for injection, in 1mL vials containing; either 2000, 3000, 4000, or 10,000 International Units (IU) of epoetin-alfa, 5.8 mg sodium citrate, 5.8 mg sodium chloride, and 0.06 mg citric acid in water.

    Epoetin beta

    In 1988 the German pharmaceutical company, Boehringer Mannheim (now part of the Roche Group) produced its own recombinant erythropoietin; epoetin-beta , marketed as NeoRecormon.

    Epoetin-beta (Recormon) comes in 1000 IU/0.3mL, 2000 IU/0.3mL, 3000IU/0.3mL, 4000 IU/0.3mL, 5000 IU/0.3mL, 6000 IU/0.3mL, 10,000 IU/0.6mL, and 30,000 IU/0.6mL solutions; and contains urea, sodium chloride, sodium phosphate, and water, in pre-filled syringes for injection. Not available in the USA.

    The clinical efficacy of both epoetin-alfa and epoetin-beta is similar.

    Darbepoetin alfa

    In 2005, Amgen patented a new erythropoietic, darbepoetin alfa , under the brand name Aranesp® Although very similar to EPO, Aranesp®, when administered, has a longer active life than EPO and is approved for use in patients with chronic renal disease, whether or not they are on dialysis.

    Epoetin delta

    This is one of the newest agents currently available. Called DYNEPO®, this agent is also produced by recombinant technology, from human cell lines. Currently marketed by Shire PLC, it is only available in the European Union. (Sanofi-aventis owns the rights to the product in the U.S., but is not producing it at this time.) DYNEPO® acts like other epoetins and is also indicated for anemia related to chronic kidney disease. It has received considerable attention in the sports world because DYNEPO® resembles human EPO and may not be detected by standard urine tests. A recent study by Spinowitz et al (Curr Med Res Opin 22:2507-13, 2006), comparing epoetin-alfa to delta, demonstrated the latter's efficacy for the correction of anemia; however, further studies are needed.

    Does EPO contain blood fractions?

    While erythropoietin itself is not a blood product, some brands of the synthetic form do have a very small amount of a blood fraction added to them. The epoetin-alfa formulation (Epogen®, Procrit®) contains 2.5 mg human serum albumin. The albumin first prevents the pharmaceutical from sticking to the vial, and then acts as a carrier molecule to help the EPO remain in the bloodstream until it reaches its destination at the bone marrow.

    Two formulations of Eprex®, one of which replaces albumin with polysorbate as a stabilizer, are available in Canada and other countries. Recormon® is also albumin-free, with polysorbate being the stabilizer. Aranesp® comes in two formulations, one contains albumin; the other is albumin-free.

    See also: forum thread.

    What is EPO primarily used for?

    • Kidney disease patients : Recombinant human erythropoietin was first approved as an adjunct in the treatment of kidney disease patients on hemodialysis, in whom anemia is an inevitability due to both the disease and the dialysis.
    • AIDS patients : Approval was also given for it to be given to AIDS patients on AZT (ziduvidene).
    • Red cell production : Its use is increasing in preoperative and postoperative settings to stimulate the surgical patient's red cell production.
    • Acute surgical and post-op : It may be of benefit in acute surgical settings, and may permit more rapid recovery in the post-op period. In particular, it may be a useful adjunct following perioperative hemodilution.
    • Chemotherapy : It is also gaining currency in the treatment of anemia secondary to chemotherapy for cancer.
    • Blood transfusion alternative : In many clinical settings EPO may be used to reduce or even eliminate the need for blood transfusion. It can be used in neonates for treatment of anemia of prematurity. Various clinical applications for EPO and a succinct historical perspective of erythropoietin are presented and discussed in research by T. Ng, et al. (2003).
    • Other potential benefits : There is evidence to show that, in addition to boosting RBC production, EPO may have a positive effect on platelet and leukocyte production. EPO has also demonstrated a tissue-protective ability, of particular benefit in chronic heart failure and neurological damage, and may benefit surgical and burn patients through its wound healing properties.

    Off-label uses

    The American Medical Association (AMA) has estimated that as many as 40 percent of all prescriptions are issued for off-label use. Off-label prescribing is considered to be clinically beneficial and rational in certain life-threatening situations. However, off-label use can pose risks to patients in terms of adverse drug events as well as contribute to rising pharmaceutical costs.

    The anti-anemic drugs erythropoietin and darbepoetin are costly, and there are significant off-label uses for these drugs, some of which are not supported with clinical evidence. They were, therefore, selected as study drugs for a multi-hospital study with the goals of quantification of the prevalence rate and appropriateness of off-label use of erythropoietin and darbepoetin across U.S. hospitals, and identification of possible predictors of off-label use from the domains of patient characteristics, physician specialty, hospital characteristics and drug characteristics.

    The results of this study revealed that more than half of the utilization of the two erythropoietic drugs is for off-label purposes, the majority of which is supported with evidence. Among the covariates, physician specialty, patient age group, race, drug coverage and length of hospital stay were significant (0.05 level) predictors of off-label use (supported and unsupported) relative to on-label.

    It is useful to understand the extent and appropriateness of off-label utilization in order to ensure safe and cost-effective use in patients. The availability of empirically derived knowledge on the national level could precipitate the promulgation of more meaningful post-marketing surveillance measures.

    What are the dosing guidelines?

    The optimal dosing regimen has yet to be defined. The authors of some studies favor lower doses such as 75 to 150 IU for every kilogram (u/kg) of body weight given daily or every other day. Others found that 600 u/kg given once a week was more effective. Nevertheless, the most commonly ordered dose is likely to be 300 u/kg three or four times a week. Thus, for a 70 kg patient, 60,000 IU per week would be ordered. The table below offers a suggested dosing guideline, based on one shown at palliativedrugs.com.


    *for average weight within each range, rounded up or down for convenience.

    As mentioned earlier, epoetin alfa is administered by injection of 1 mL of a water-based solution which may contain a single dose of 2000, 3000, 4000, 10,000, or 40,000 units of epoetin alfa per single dose, along with other ingredients including albumin, based on treatment requirements and weight of patient. In addition, multidose injections may also be administered with 10,000 units or 20,000 units per 1 mL of injection solution. This is similar for the other forms of EPO. While the dosage of EPO is measured in what sounds to nonmedical persons like a very large amount (thousands of units), in actuality, the amount of liquid injected is very small, always in 1 mL increments, which means the units of epoetin alfa are very miniscule despite the high number of units per dose. To help in understanding the injection amount, a milliliter (mL) is a metric unit of volume equal to one thousandth of a liter; and 1 mL converted to American measurements is approximately 1/5th of a teaspoon; therefore, it is a very small amount of liquid injected at one time. Understanding these amounts no doubt will help alleviate some of the concern patients may have when hearing how much EPO they are to be given. It should be borne in mind that chronic diseases, such as renal failure, heart disease, diabetes, and inflammatory diseases like rheumatoid arthritis, all contribute to anemia and all produce a blunted response to EPO therapy. A blunted response is also expected in the presence of infection. Hence, in all such cases the dosage should be increased.

    Ortho Biotech holds the distribution rights for Zidovudine-treated HIV-infected Patients, Cancer Patients on Chemotherapy, Anemia of Chronic Renal Failure Patients not on Dialysis and Reduction of Allogeneic Blood Transfusion in Surgery Patients.

    Ortho Biotech provides a Full Prescribing Information (pdf) regarding Procrit®.

    Amgen holds the distribution rights for treatment of Anemia of Chronic Renal Failure Patients on Dialysis. They provide indication and dosing information regarding EPOGEN®.

    Amgen also holds the patent on Aranesp® (darbepoetin alfa) which is indicated for the treatment of anemia associated with chronic renal failure (CRF), including patients on dialysis and patients not on dialysis, and for the treatment of anemia in patients with nonmyeloid malignancies where anemia is due to the effect of concomitantly administered chemotherapy. Because of the way Aranesp is made (unique and advanced molecular design, i.e., 2 additional sialic-acid-containing carbohydrate chains), patients need fewer shots and doctor visits.

    EPO and iron

    For EPO therapy to be effective it should be supplemented with iron. Intravenous iron is more effective than oral iron , though iron dextran is inadvisable because of its known adverse reactions, including anaphylactic reactions.

    Ferric gluconate or ferric sucrose are better tolerated by most patients. Here again, no universally agreed-upon dose has emerged, but many clinicians favor giving 100 mg one to three times per day. On the other hand, a recent study indicated that patients respond well to 500 mg given over 3 hours on two successive days with no adverse effects.

    What risks or side-effects are there?

    Already hypertensive patients may experience further elevation of blood pressure, and a minority of patients (perhaps 20-30%) with chronic renal failure may experience increased blood pressure, when given intravenous EPO. This is thought to be caused by the rapid increase in hematocrit. For the same reason, some patients may develop blood clots. These undesirable reactions are less common when the drug is administered subcutaneously. In general, elevated blood pressure can be managed with antihypertensive agents.

    Recently Eprex® has been associated with incidences of pure red-cell aplasia, a condition which, though rare, can lead to permanent blood transfusion dependency.

    Possible minor side effects include: diarrhea, dizziness, headache, itching, muscle aches and pains, nausea, pain at the site of injection, tiredness, or vomiting. These side effects usually diminish or disappear as the body adjusts to the medication.

    Results of Recent Research

    • Amgen study results released January 29, 2007 reflect higher mortality rates in use of Aranesp® in cancer patients with anemia not caused by chemotherapy. Amgen stresses need for caution in using this product within the dosage parameters stated on their approved product label.
    • Here are some links to information related to this study:

    EPO abuses

    So-called "EPO-doping" has become popular among some high performance athletes who inject it prior to a competition to boost their red blood cell count and thereby enhance their performance. Although previously undetectable, a test has been devised to catch athletes who adopt this illegal measure. The new epoetin-delta, DYNEPO, may not be detectable in the standard urine tests, and is of some concern to sports authorities.

    Where do I get it?

    EPO is available by prescription only, under one or more of the trade and/or generic names listed above. Certain forms of this product may not be available in the country where you live. There may be other generic forms that have not been listed here. You should ask your health care provider about whether it is appropriate for you to use this product.

    How much does it cost?

    Specific cost data is being researched, but generally EPO is still quite expensive (about twice as costly) relative to the cost of blood transfusion, for which EPO is an alternative treatment. Of course, total cost of treatment depends on the condition being treated, the length of treatment, and the frequency of dosing. Some cancer patients can receive EPO on a once-every-three-weeks dosing interval; other patients may need once a week or more frequent dosing, or larger doses.

    What alternatives to EPO are there?

    EPO is the standard of care for many patients with anemia of end-stage renal disease (ESRD). For certain patients, such as those who produce antibodies to erythropoietin, who develop pure red cell aplasia (PRCA), or who develop arterial hypertension, treatment with any form of EPO is not appropriate. However, these patients may be given androgens (hormones) that have been shown to stimulate bone marrow function. Of course, as with any medicine, these substances are not without side effects of their own. One of the most widely used of these is nandrolone decanoate (NAND), which seems to be better tolerated with less dramatic side effects than other androgenics.

    In some cases, intravenous iron without EPO appears to be as effective in correcting anemia.


    Products in Clinical Trials

    Several new erythropoiesis-stimulating agents are currently in various stages of clinical trials in patients with chronic kidney disease:

    • Continuous Erythropoiesis Receptor Activator (CERA), a third-generation erythropoiesis-stimulating agent that is closest to reaching the market.
    • Erythropoietin-Mimetic Peptides , agents have the same mechanism of action as endogenous and recombinant erythropoietin, although they are structurally unrelated. One agent in this class, Hematide , is in phase 2 of clinical development.
    • Hypoxia-Inducible Factor Stabilizer (HIF), a transcription factor that activates erythropoietin during hypoxic conditions and regulates iron absorption, metabolic response, and vasculogenesis.

    Molecular analysis

    erythropoietin
    Identifiers
    Symbol(s)EPO
    Entrez2056
    OMIM133170
    RefSeqNM_000799
    UniProtP01588
    Other data
    LocusChr. 7q21

    ~~~
    Molecular Comparison Epoetin Alfa and Aranesp

    FAQs

    • Why is there reluctance to use EPO among some clinicians?

    Some clinicians feel that it is too expensive; some assume it takes too long to produce any significant increase in RBCs; and some fear it will raise blood pressure in already hypertensive patients. However, there is much clinical and anecdotal evidence to suggest that, with careful patient selection, the benefits of EPO therapy outweigh both the risks and the cost factor.

    • How long does EPO take to produce a significant rise in hemoglobin or hematocrit?

    Patient response to the drug varies, and a minority of patients show little or no response. However, many studies have shown that in patients without underlying disease or active bleeding, EPO can raise the hemoglobin by one gram per deciliter (1 g/dL) in as little as one week -- the equivalent of a unit of packed red blood cells.

    • Is EPO therapy cost-effective?

    The answer depends on whether or not the hidden costs of the hazards and complications of blood transfusion are taken into account. If such costs are factored in, EPO therapy appears to be cost effective.

    • How is the drug administered?

    It is injected either subcutaneously or intravenously. [1] There is considerable debate in the medical literature regarding which route offers the best results.

    • For Jehovah's Witnesses who may be concerned about the presence of a blood fraction, is an albumin-free formulation of EPO (Recormon or Eprex) available in the United States?

    Not at present; however, albumin-free Aranesp is available in the US.

    See also

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