Erythropoietin administration

Hayashi W, Kinoshita H, Yukawa E, Higuchi S. Pharmacokinetic analysis of subcutaneous erythropoietin administration with non-linear mixed effect model including endogenous production. Br J Clin Pharmacol 1998 46 11-9. 

Cherian L, Goodman JC, Robertson C (2007) Neuroprotection with erythropoietin administration following controlled cortical impact injury in rats. J Pharmacol Exp Ther 322 789-794 Childers SR, Breivogel CS (1998) Cannabis and endogenous cannabinoid systems. Drug Alcohol Dependence 51 173-187... 

A multiple-step mechanism could also control iron absorption through the intestine. For example, it has been proposed that the bone marrow controls the secretion of a specific humoral factor responsible for regulating the intestinal absorption of iron. If such a hormone exists, it is unlikely to be erythropoietin. Erythropoietin administration to animals has no effect on iron absorption. Conversely, intestinal absorption and the iron stores influence the rate of erythropoiesis. Iron loading of anemic dogs considerably stimulates hemoglobin synthesis. 

Pandey V, Dummula K, Fraga G, Parimi P. Late-onset blueberry muffin lesions following recombinant erythropoietin administration in a premature infant. J Pediatr Hematol Oncol 2012 34(7) 534-5. 

The conclusion of this study is that erythropoietin administration leads to increased skeletal muscle metabolism, and that the anaemia per se accounts partly for the deranged muscle dysfunction, which seems to have a multifactorial background. 

Parenteral iron therapy currently is available in three different formulations, which are listed in Table 63-3. Iron dex-tran was the first parenteral iron formulation to be approved, followed by ferric gluconate, and then iron sucrose. Although these newer agents are only approved by the Food and Drug Administration (FDA) to treat anemia associated with CKD in patients receiving erythropoietin products, they are effective in treating iron-deficiency anemia as well. Iron dextran is FDA approved for treating documented iron deficiency in patients who are unable to tolerate the oral formulation. 

Although EPO deficiency is the primary cause of CKD anemia, iron deficiency is often present, and it is essential to assess and monitor the CKD patient s iron status (NKF-K/DOQI guidelines). Iron stores in patients with CKD should be maintained so that transferrin saturation (TSAT) is greater than 20% and serum ferritin is greater than 100 ng/mL (100 mcg/L or 225 pmol/L). If iron stores are not maintained appropriately, epoetin or darbepoetin will not be effective, and most CKD patients will require iron supplementation. Oral iron therapy can be used, but it is often ineffective, particularly in CKD patients on dialysis. Therefore, intravenous iron therapy is used extensively in these patients. Details of the pharmacology, pharmacokinetics, adverse effects, interactions, dose, and administration of erythropoietin and iron products have been discussed previously. 

To date, three pharmaceutical companies have entered clinical trials with PHD inhibitors for the treatment of anemia with the most advanced being FG-2216. In clinical studies, compound 2 (likely FG-2216) showed a dose- and time-dependent elevation of plasma erythropoietin after oral administration [66]. Healthy volunteers were orally administered various doses of compound 2 and serum erythropoietin (EPO) concentrations were measured at various times. Compound 2 increased serum EPO levels in a dose-dependent manner and, following administration of the 20 mg/kg dose, a 5-fold increase of EPO levels was observed after 12 h. In the same patent application, the effect of 2 on anemic predialysis patients with no previous rh-EPO exposure was also disclosed. Patients were treated with 2 three times/week for 4 weeks (no dose reported) and the hemoglobin levels were assessed on day 42. The patients who received treatment showed a mean increase in hemoglobin of 1.9 g/dL from baseline values, whereas subjects who received placebo showed a mean decrease of 0.35 g/dL from baseline levels. These data suggest for the first time that an oral PHD inhibitor could be effective for the treatment of anemia. 

Toxicity studies traditionally are conducted using normal animals. However, studies in animal disease models may provide additional safety information regarding the possibility of disease exacerbation. For example, the administration of human recombinant erythropoietin was associated with hypertension in patients with chronic renal failure, and also in uraemic dogs, but not in normal dogs. 

Pharmacokinetics Epoetin alfa IV is eliminated via first-order kinetics with a circulating half-life of 4 to 13 hours in patients with CRF. Within the therapeutic dosage range, detectable levels of plasma erythropoietin are maintained for at least 24 hours. After subcutaneous administration of epoetin alfa to patients with CRF,... 

Iron deficiency anemia is treated with oral or parenteral iron preparations. Oral iron corrects the anemia just as rapidly and completely as parenteral iron in most cases if iron absorption from the gastrointestinal tract is normal. An exception is the high requirement for iron of patients with advanced chronic kidney disease who are undergoing hemodialysis and treatment with erythropoietin for these patients, parenteral iron administration is preferred. 

Epoetin alfa Agonist of erythropoietin receptors expressed by red cell progenitors Stimulates erythroid proliferation and differentiation, and induces the release of reticulocytes from the bone marrow Treatment of anemia, especially anemia associated with chronic renal failure, HIV infection, cancer, and prematurity prevention of the need for transfusion in patients undergoing certain types of elective surgery IV or SC administration 1-3 times per week Toxicity Hypertension, thrombotic complications, and, very rarely, pure red cell aplasia to reduce the risk of serious CV events, hemoglobin levels should be maintained < 12 g/dL... 

A mechanism-based PK/PD model for rHu-EPO was used to capture the physiological knowledge of the biological system. An open, two-compartment disposition model with parallel linear and nonlinear clearance, and endogenous EPO at baseline, was used to describe recombinant human erythropoietin (rHu-EPO) disposition after intravenous administration [35]. The pharmacodynamic effect of rHu-... 

The biotechnology industry has evolved significantly since the introduction in 1982 of human insulin synthesized in Escherichia coli—the first Food and Drug Administration (FDA)-approved recombinant therapeutic agent in the United States. Since then, over 75 other recombinant proteins have been introduced. The list is comprised of cytokines, hormones, monoclonal antibodies, and vaccines. There are more than 1100 companies competing for this market, and the current sale of these products comprises approximately 10% of the sales of all therapeutic products sold in the United States. One such product, erythropoietin, an erythropoiesis-stimulating factor also known... 

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