They are stabilized by polysorbate Tween or , or human albumin 2. Differences in the amino acid residues chain are indicated by a random prefix e. The glycosylation pattern is indicated by a Greek letter alfa, beta, etc. Two brands of innovator CHO cell-derived rhEpo, namely epoetin alfa and epoetin beta, were launched as anti-anemic agents about 25 years ago. The originator epoetins alfa and beta are used for the same major indications anemias associated with CKD or myelosuppressive chemotherapy treated cancer. The primary rationale for the use of biosimilars is cost saving.
The several brand names are accounted for by co-marketing of the same drug substances by different companies. Overall, the naming INNs of the epoetins is confusing for physicians in the EU ][reviewed in [ 35 ]]. Physicochemical and functional investigations of purported epoetin alfa copies manufactured and used in a good many Asian and Latin American countries revealed major isoform differences, batch-to-batch variations in potencies as well as endotoxin contamination of some of the products [ 36 ].
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On SC administration, peak plasma concentrations are approximately one twentieth of the initial values measured after IV administration. Compared with the terminal half-life of IV administered epoetin h , the half-life of darbepoetin alfa is three- to fourfold longer 25 h , which allows for less frequent application [ 39 ].
The prolonged in vivo survival of darbepoetin alfa and methoxy PEG-epoetin beta is in part due to a reduced EpoR binding affinity. Clinically, however, the long-acting products may allow for dose reductions below the predicted 1: ratio [ 39 ]. ESAs can be indicated for the treatment of chronic forms of anemia, but the drugs are not an alternative to RBC transfusions for patients with severe trauma-induced hemorrhage, major blood loss during surgery such as in cardiothoracic or liver surgery, and severe or life-threatening anemia.
Depending on individual country regulations ESAs have been approved for i anemia due to CKD, both predialysis and dialysis, ii anemia in patients with cancer receiving chemotherapy, iii anemia associated with zidovudine treatment in HIV infection, iv support of autologous blood collection, v elective surgery, and vi anemia in preterm infants.
Indeed, lack of Epo is the primary factor causing the anemia in CKD. The renal fibroblasts lose their Epo-producing capacity after injury and trans-differentiate to scar-producing myofibroblasts [ 40 ]. Other factors implicated in renal anemia are blood loss, shortening of RBC life-span, malnutrition, reduced iron availability, and inhibition of the growth of erythrocytic progenitors by inflammatory cytokines and uremia toxins.
Physical performance and brain function may also improve on anemia alleviation. The target hematocrit Hct in ESA treated patients was generally set in the range 0. In patients with CKD the major cause of resistance towards ESAs is reduced iron availability, due to the action of hepcidin. However, physicians should be aware that iron overload may cause tissue damage [ 45 ]. The primary goal of the therapy is to maintain the Hb concentration above the transfusion trigger, yet RBC transfusions are also an option. Clinicians should outweigh potential harms e. ESAs should be administered at the lowest dose possible, and the treatment should increase Hb concentration to the lowest level possible if it aims at avoiding RBC transfusions.
In the surgical setting, rhEpo may be administered preoperatively in order to stimulate erythropoiesis in phlebotomy programs for autologous RBC re-donation or correction of a pre-existing anemia, and postoperatively for recovery of RBC mass in certain interventions. Another approved indication for ESAs can be the anemia of prematurity to reduce the number of RBC transfusions in newborns.
Cases of acute toxic effects of approved rhEpo formulations or its analogs have never been reported. ESAs are contraindicated in patients with hypersensitivity to non-human cell-derived products. Patients with a hypersensitivity to human albumin should not be treated with formulations stabilized with this protein. In pregnancy, rhEpo should be administered very cautiously, because the risks for the fetus have not been evaluated in humans. In ESA-treated CKD patients, the most common unwanted effect is an increase in arterial blood pressure and possibly hypertension affects users in Thus, ESAs are contraindicated in patients with uncontrolled hypertension.
The increase in blood pressure can be partly explained by the elevated blood viscosity and the reversal of hypoxia-induced vasodilatation in association with the increase in Hb concentration. Patients with non-renal anemia do not usually develop hypertension on ESA therapy. The use of ESAs may increase the incidence of thromboembolism and the risk of cardiovascular events, including death. It seems likely that the occurrence of cardiovascular events is partly related to the elevation in Hb concentration and Hct.
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Similarly, in cancer patients thromboembolic events are considered a critical risk factor associated with the use of ESAs [ 47 ]. The update of a Cochrane Database review, which included 91 randomized controlled trials with 20, participants on managing anemia in cancer patients receiving or not receiving anticancer therapy that compared the use of ESAs plus transfusion if needed has not only confirmed that use of ESAs reduces the relative risk of RBC transfusions but also provided evidence that ESAs increase the risk for thromboembolic complications and deaths [ 48 ].
Possibly, ESA therapy is associated with an increase in platelet numbers. ESAs could stimulate thrombopoiesis in an indirect way, as iron depletion due to increased erythropoiesis can result in thrombocytosis [ 49 ]. A recent report proposes to reduce the ESA-associated risk of thrombosis by anti-thrombotic therapy [ 50 ].
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Another critical issue is whether ESAs could stimulate tumor growth. Laboratory studies applying appropriate biochemical techniques have shown that cancer cells lack functional EpoR protein, although they express low levels of EPOR mRNA [ 16 , 17 , 25 ]. The question of whether Epo and its analogs can promote tumor growth by stimulating angiogenesis is a focus of present research, with some authors answering in the affirmative [ 51 ] and others in the negative [ 19 ].
Several meta-analyses have examined ESA use and safety outcomes in cancer patients. Bennett et al. Meta-analyses have shown that ESA use does not generally impact disease progression [ 53 , 54 ]. The increased risk of death and thromboembolic events should be balanced against the potential benefits of ESA treatment taking into account each patient's clinical circumstances and preferences' [ 48 ].
Finally, drug purity and immunogenicity are issues with biopharmaceuticals. The production of ESAs confers to extremely high biotechnological standards in most regions of the world, including Northern America, Europe and Japan. However, changes in the manufacturing process or the formulation of an ESA may cause an immune reaction.
When neutralizing anti-Epo Abs occurred on SC administration of a biosimilar epoetin, investigations carried out by the manufacturer revealed that abnormally high tungsten levels in the pre-filled syringes caused the epoetin to unfold and to aggregate [ 56 ]. Hence, a change in the type of syringes could overcome the transient problem.
Anemia treatment with recombinant ESAs is cost-intensive. Thus, the question arose whether there are alternative therapeutic options [ 57 , 58 ]. Actually, many different HIF stabilizers have been identified [ 5 , 6 , 60 ]. However, HIF stabilizers induce the expression of numerous genes apart from EPO [ 5 , 60 ], which may result in adverse events. Another strategy has been to replace recombinant ESAs by Epo mimetic peptides EMPs , synthetic cyclic peptides of about 20 amino acids.
However, the drug was recalled early in , since 0. However, doubt may be raised as to the advantages of this type of biopharmaceutical over the established ESAs. Sotatercept binds and inactivates activin A. In a phase I clinical trial sotatercept produced dose-dependent increases in reticulocytes, RBCs, Hb concentration, and Hct in healthy postmenopausal women [ 39 ].
However, in contrast to HIF-stabilizers, which can be taken orally, sotatercept must be injected. In addition, the immunogenic potential of the drug should be studied in more detail. Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions.
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