Efficacy of different dosing regimens for recombinant human erythropoietin in a simulated perisurgical setting: The importance of iron availability in optimizing response

Rutherford, Cynthia J.; Schneider, Thomas J.; Dempsey, Hilton; Kirn, David H.; Brugnara, Carlo; Goldberg, Mark A.

doi:10.1016/0002-9343(94)90134-1

Cited by 75 publications

(43 citation statements)

References 22 publications

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“…by guest www.bloodjournal.org From (increases in RBC count, hematocrit value, and soluble transferrin receptor protein, and decreases in ferritin, reticulocyte Hgb content) are also consistent with stimulation of erythropoiesis in healthy iron-replete volunteers. 4,5,11 Rapid mobilization of iron is required for a robust Hgb response during erythropoietic stimulation with exogenous ESAs. Healthy volunteers receiving single or repeat injections of rHuEPO, even with oral or intravenous iron supplementation, have been shown to have transient decreases in the content of reticulocyte Hgb and serum ferritin levels.…”

Section: Discussionmentioning

confidence: 99%

“…This benign safety profile is consistent with that of other ESAs administered to healthy volunteers. [5][6][7][8][9][10][11][12][13] Hematide showed dose-dependent increases in reticulocytes with greater and more sustained responses with increasing dose. The 0.1-mg/kg dose was determined to be the PAD in healthy volunteers because it was associated with a statistically and biologically significant increase in Hgb from baseline that was sustained for longer than 1 month.…”

Section: Discussionmentioning

confidence: 99%

“…1 The design of this first study of Hematide in humans was based on these nonclinical data and the published reports of ESAs in approximately 400 healthy volunteers. [4][5][6][7][8][9][10][11][12][13] This study was designed to evaluate the safety and pharmacokinetic and pharmacodynamic profiles of single intravenous dose levels of the drug and to determine the minimum pharmacologic active dose (PAD) in healthy subjects. Results of the pharmacokinetic analysis will be published separately.…”

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confidence: 99%

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Evaluation of the safety and pharmacodynamics of Hematide, a novel erythropoietic agent, in a phase 1, double-blind, placebo-controlled, dose-escalation study in healthy volunteers

Stead

Lambert

Wessels

et al. 2006

Blood

104

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Hematide is an investigational pegylated synthetic peptide that stimulates erythropoiesis in animal models and is being developed for the treatment of anemia associated with chronic renal failure and cancer. This study evaluated the safety and pharmacodynamics of single, intravenous doses (0.025, 0.05, and 0.1 mg/kg) of Hematide in 28 healthy male volunteers. All doses of Hematide were well tolerated, with safety profiles similar to those of placebo. Hematide showed a dose-dependent increase in reticulocytes. The 0.1-mg/kg dose was associated with a statistically significant increase in hemoglobin (Hgb) from baseline compared to the placebo group (13.6 ؎ 3.9 g/L [1. 36 IntroductionThere are several common clinical situations in which anemia is the result of hypoproliferation of red blood cell (RBC) precursors secondary to erythropoietin (EPO) deficiency. These include anemias associated with chronic kidney disease (CKD), chronic inflammation, and cancer, with or without myelosuppressive therapy. In these situations, recombinant human EPO (rHuEPO) has been used successfully to increase hemoglobin (Hgb) levels, reduce fatigue, and improve daily function.Hematide is a synthetic, dimeric peptidic erythropoiesisstimulating agent (ESA) covalently linked to polyethylene glycol (PEG) and is being developed for the treatment of anemia associated with chronic renal failure and cancer. Because its primary amino acid sequence is unrelated to that of rHuEPO, Hematide is unlikely to induce a cross-reactive immune response against endogenous EPO. 1 This potentially reduces the risk of pure red cell aplasia (PRCA), a rare complication caused by an immune response to rHuEPO. PRCA reached a peak incidence outside of the United States in 2001 to 2002, largely related to a change in formulation of the product. 2,3 Hematide binds to and activates the human EPO receptor, stimulating the proliferation and differentiation of human red cell precursors in vitro in a manner similar to ESAs. 1 A predictable, dose-related effect on reticulocyte and Hgb levels has been observed in rats and monkeys. 1 The design of this first study of Hematide in humans was based on these nonclinical data and the published reports of ESAs in approximately 400 healthy volunteers. [4][5][6][7][8][9][10][11][12][13] This study was designed to evaluate the safety and pharmacokinetic and pharmacodynamic profiles of single intravenous dose levels of the drug and to determine the minimum pharmacologic active dose (PAD) in healthy subjects. Results of the pharmacokinetic analysis will be published separately. Subjects, materials, and methods EligibilityEligible subjects were men, 18 to 40 years of age, with a body mass index (BMI) of 18 to 30 kg/m 2 , without any clinically significant medical condition. At study entry, subjects were to have a Hgb value of 160 g/L (16 g/dL) or less, and normal values for ferritin, white blood cell count, and platelet count. All subjects were informed of the investigational nature of this study and signed informed consent. The stud...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Evaluation of the safety and pharmacodynamics of Hematide, a novel erythropoietic agent, in a phase 1, double-blind, placebo-controlled, dose-escalation study in healthy volunteers

Stead

Lambert

Wessels

et al. 2006

Blood

104

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“…To the Editor: We read with great interest the manuscript by Jabbour and colleagues entitled "Allogeneic stem cell transplantation (SCT) as initial salvage for patients with acute myeloid leukemia refractory to high-dose cytarabine-based induction chemotherapy" [1]. The authors reported that allogeneic SCT was associated with superior overall survival (OS) compared to salvage chemotherapy, with a 3-year OS rate of 39% in the SCT group.…”

Section: Michael Auerbachmentioning

confidence: 99%

“…To the Editor: In an attempt to provide a short term, practical, and effective regimen for perioperative anemia therapy as an alternative to autologous blood transfusion, Rutherford et al, evaluated three different regimens of recombinant human erythropoietin and concluded that irrespective of dose, "normal" iron stores for basal erythropoiesis may not always be sufficient to supply optimal amounts of iron for the accelerated erythropoiesis associated with acute recombinant erythropoietin administration, even with oral iron supplementation [1]. The comorbidity burden of surgical complications of perioperative anemia, present in one-third to one-half of all surgical patients remains clinically and economically formidable.…”

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confidence: 99%

Intravenous iron in the perioperative setting

Auerbach¹

2014

American J Hematol

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Epoetin Alfa

Henry¹,

Bowers²,

Romano³

et al. 2004

Arch Intern Med

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Recombinant human erythropoietin (epoetin alfa) has been used in clinical settings for more than a decade. Its indications have expanded considerably from its original use as hormone therapy in the treatment of anemia in adults with chronic kidney disease. Since the introduction of epoetin alfa, a greater understanding of anemia pathophysiology and the interactions of erythropoietin, iron, and erythropoiesis has been elucidated. Anemia is now independently associated with increased mortality and disease progression. Potential survival benefits associated with correction of anemia in various patient populations are leading to consideration of earlier, more aggressive treatment of mild to moderate anemia with epoetin alfa. Moreover, this agent's therapeutic use may extend beyond currently accepted roles. Epoetin alfa is undergoing evaluation with promising results in a variety of new clinical settings, including anemia associated with congestive heart failure, ribavirin-interferon alfa treatment of hepatitis C virus infection, and critical illness. Preclinical studies also have established erythropoietin and its recombinant equivalent to be a pleiotropic cytokine with antiapoptotic activity and neuroprotective actions in the central nervous system. The therapeutic potential of epoetin alfa appears yet to be fully realized.

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Efficacy of different dosing regimens for recombinant human erythropoietin in a simulated perisurgical setting: The importance of iron availability in optimizing response

Cited by 75 publications

References 22 publications

Evaluation of the safety and pharmacodynamics of Hematide, a novel erythropoietic agent, in a phase 1, double-blind, placebo-controlled, dose-escalation study in healthy volunteers

Evaluation of the safety and pharmacodynamics of Hematide, a novel erythropoietic agent, in a phase 1, double-blind, placebo-controlled, dose-escalation study in healthy volunteers

Intravenous iron in the perioperative setting

Epoetin Alfa

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