Pharmacokinetics and pharmacodynamics of recombinant human erythropoietin after single and multiple subcutaneous doses to healthy subjects*

Cheung, Wing K.; Goon, Betty; Guilfoyle, Mary; Wacholtz, Mary C.

doi:10.1016/s0009-9236(98)90072-8

Cited by 102 publications

(80 citation statements)

References 17 publications

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“…Serum erythropoietin concentrations peaked 12 to 24 h after the first dose of each regimen and increased in a dosage-related manner with increasing dosage. Similar findings were reported in previous studies of healthy volunteers (11,12). After the final epoetin alfa dose of the first week, erythropoietin concentrations declined multiexponentially to baseline values by approximately day 8.…”

Section: Discussionsupporting

confidence: 91%

“…In the three-times-weekly group, additional samples were collected at 2, 4, and 6 h after dose on day 1; before dose on day 3 and on day 5; and at 3, 6, 9, 12, 24, 27, 36, 48, and 72 h after dose on day 5. In the other three treatment groups, additional samples were collected at 3,6,9,12,24,27,36,48,72,96,120,144, and 168 h after dose on day 1. Samples were also obtained once weekly through day 29 in the three-times-weekly, once-weekly, and every-2-wk groups and through day 57 in the every-4-wk group.…”

Section: Pharmacokineticsmentioning

confidence: 99%

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Pharmacokinetic and Pharmacodynamic Profiles of Extended Dosing of Epoetin Alfa in Anemic Patients Who Have Chronic Kidney Disease and Are Not on Dialysis

McGowan¹,

Vaccaro²,

Beaver³

et al. 2008

Clinical Journal of the American Society of Nephrology

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Background and objectives: Emerging evidence suggests that epoetin alfa can be administered at extended intervals of up to 4 wk. This open-label, randomized study was performed to characterize the pharmacokinetic and pharmacodynamic profiles of four dosing regimens of epoetin alfa administered subcutaneously in anemic patients who had chronic kidney disease and were not on dialysis.Design, setting, participants, & measurements: Thirty-eight patients, enrolled from nine centers in the United States, were >18 yr of age and had hemoglobin <11.0 g/dl and GFR 12 to 60 ml/min per 1.73 m 2 . Patients received one of four epoetin alfa dosing regimens: 50 IU/kg three times per week, 10,000 IU once weekly, or 20,000 IU every 2 wk for 36 d or 40,000 IU every 4 wk for 64 d. Each regimen provided a similar dosage of epoetin alfa over 4 wk. Dosage adjustments were not permitted.Results: Drug exposure to epoetin alfa over 4 wk, based on area under the curve, was somewhat higher with the extended interval regimens compared with the three-times-weekly regimen. Mean change in hemoglobin during the study period was similar for all regimens. No patients were transfused. Three patients experienced five serious adverse events, none of which was considered treatment related.Conclusions: Extended dosing interval regimens of epoetin alfa yielded modest pharmacokinetic differences but a similar pharmacodynamic response, suggesting that less frequent, higher dosages of epoetin alfa may be as effective as the current three-times-weekly regimen in anemic patients who have chronic kidney disease and are not on dialysis.

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Section: Discussionsupporting

confidence: 91%

Section: Pharmacokineticsmentioning

confidence: 99%

Pharmacokinetic and Pharmacodynamic Profiles of Extended Dosing of Epoetin Alfa in Anemic Patients Who Have Chronic Kidney Disease and Are Not on Dialysis

McGowan¹,

Vaccaro²,

Beaver³

et al. 2008

Clinical Journal of the American Society of Nephrology

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“…The serum rHuEpo concentrations were measured using an established and validated radioimmunoassay with a limit of quantification of 7.8 mIU/ml as described by Cheung et al (1998). The assay probably measures endogenous monkey Epo, but baseline values were below the limit of quantification.…”

Section: Methodsmentioning

confidence: 99%

“…Several investigators have reported pharmacokinetic and dynamic studies of rHuEpo in humans and many animal species, including mouse, rat, dog, rabbit, sheep, and horse (Fu et al, 1988;Jaussaud et al, 1994;Bleuel et al, 1996;Souillard et al, 1996;Widness et al, 1996;Yoon et al, 1997;Cheung et al, 1998;Chapel et al, 2000;Kato et al, 2001). A clear mathematical quantification of the kinetics and dynamics of rHuEpo effects would greatly facilitate rational design of optimal dosage regimens and aid therapy.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetic and Pharmacodynamic Modeling of Recombinant Human Erythropoietin after Intravenous and Subcutaneous Dose Administration in Cynomolgus Monkeys

Ramakrishnan

Cheung²,

Farrell³

et al. 2003

J Pharmacol Exp Ther

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The pharmacokinetics (PK) and pharmacodynamics (PD) of recombinant human erythropoietin (rHuEpo) were investigated in monkeys. A two-compartment model with dual input and nonlinear disposition could adequately characterize the PK of rHuEpo upon three intravenous and six s.c. administrations. The kinetic model suggests rapid zero-order absorption of part of the s.c. dose (35%) followed by a slow first-order entry through the lymphatics. The s.c. treatments caused a delayed dose-dependent rise in reticulocyte numbers peaking between 100 and 200 h and returning to baseline by 300 to 400 h. This was followed by steady rises in red blood cell (RBC) and hemoglobin counts. A physiological catenary model based on a life span concept with rHuEpo stimulating the production of two cell populations (progenitor cells and erythroblasts) was applied. The model could adequately describe the reticulocyte responses upon the various s.c. treatments, giving estimates of maturation times for cells in the various stages of differentiation including the early progenitor cells (70.4 h), erythroblasts (15.0 h), and reticulocytes (141.6 h) that are close to the literature reported values. An S max of 3.13 was estimated indicating a moderate maximum stimulation of erythropoiesis, whereas the SC 50 was 842 IU/l. The model was used to effectively predict the increases in RBC and hemoglobin counts as well. In conclusion, the physiological PK/PD model developed could adequately describe the time course of rHuEpo effects, yielding realistic estimates of cell life span parameters.Erythropoiesis involves a sequence of cellular differentiations that are controlled by specific hematopoietic growth factors. Erythropoietin (Epo) is a key lineage-specific humoral regulator of mammalian erythropoiesis. The recombinant form of human erythropoietin (rHuEpo) is structurally very similar to endogenous Epo (Egrie, 1990). It exerts its biological effects by binding to specific receptors in the bone marrow cells, which causes them to undergo a 5-to 9-day process of cellular proliferation, differentiation, and maturation leading to an increase in reticulocyte counts followed by rises in hematocrit and hemoglobin levels in the blood (Flaharty, 1990).rHuEpo has been shown to be an effective alternative to blood transfusion, ameliorating anemia associated with a variety of indications and producing consequent improvements in quality of life in many renal (Lundin et al., 1990) and nonrenal applications (Markham and Bryson, 1995) in humans. Several investigators have reported pharmacokinetic and dynamic studies of rHuEpo in humans and many animal species, including mouse, rat, dog, rabbit, sheep, and horse (Fu et al., 1988;Jaussaud et al., 1994;Bleuel et al., 1996;Souillard et al., 1996;Widness et al., 1996;Yoon et al., 1997;Cheung et al., 1998;Chapel et al., 2000;Kato et al., 2001). A clear mathematical quantification of the kinetics and dynamics of rHuEpo effects would greatly facilitate rational design of optimal dosage regimens and aid therapy. The Epo...

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“…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.…”

Section: Introductionmentioning

confidence: 99%

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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Pharmacokinetics and pharmacodynamics of recombinant human erythropoietin after single and multiple subcutaneous doses to healthy subjects*

Abstract: These findings show that the pharmacologic response to epoetin alfa is a function of dose and dosing regimen. Repeated administration of epoetin alfa was more effective in stimulating a reticulocyte response than single-dose administration of the same total amount of epoetin alfa.

Cited by 102 publications

References 17 publications

Pharmacokinetic and Pharmacodynamic Profiles of Extended Dosing of Epoetin Alfa in Anemic Patients Who Have Chronic Kidney Disease and Are Not on Dialysis

Pharmacokinetic and Pharmacodynamic Profiles of Extended Dosing of Epoetin Alfa in Anemic Patients Who Have Chronic Kidney Disease and Are Not on Dialysis

Pharmacokinetic and Pharmacodynamic Modeling of Recombinant Human Erythropoietin after Intravenous and Subcutaneous Dose Administration in Cynomolgus Monkeys

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

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