Novel erythropoiesis stimulating protein for treatment of anemia in chronic renal insufficiency

Locatelli, Francesco; Olivares, Jorge; Walker, Rowan G.; Wilkie, Martin; Jenkins, B S; Dewey, Claire; Gray, Stephen J.

doi:10.1046/j.1523-1755.2001.060002741.x

Cited by 174 publications

(135 citation statements)

References 11 publications

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“…An increased risk of TVEs has been reported in some patient populations treated with ESAs (22,23), most notably in oncology patients and in patients undergoing surgical procedures. In this study, the incidence of TVEs was low, despite the fact that these subjects had multiple pre-existing risk factors (age, diabetes mellitus, hypertension, hypercholesterolemia, obesity, and prior history of vascular events).…”

Section: Discussionmentioning

confidence: 99%

A Randomized Controlled Study of Weekly and Biweekly Dosing of Epoetin Alfa in CKD Patients With Anemia

Pèrgola

Gartenberg

et al. 2009

Clinical Journal of the American Society of Nephrology

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Background and objectives: In clinical practice, physicians often use once-weekly (QW) and biweekly (Q2W) dosing of epoetin alfa to treat anemia in patients with chronic kidney disease (CKD). Although the literature supports this practice, previous studies were limited by short treatment duration, lack of randomization, or absence of the approved three times per week (TIW) dosing arm. This randomized trial evaluated extended dosing regimens of epoetin alfa, comparing QW and Q2W to TIW dosing in anemic CKD subjects. The primary objective was to show that treatment with epoetin alfa at QW and Q2W intervals was not inferior to TIW dosing.Design, setting, participants, & measurements: 375 subjects with stage 3 to 4 CKD were randomized equally to the three groups and treated for 44 wk; to explore the impact of changing from TIW to QW administration on hemoglobin (Hb) control and adverse events, subjects on TIW switched to QW after 22 wk. The Hb was measured weekly, and the dose of epoetin alfa was adjusted to achieve and maintain an Hb level of 11.0 to 11.9 g/dl.Results: Both the QW and Q2W regimens met the primary efficacy endpoint. More subjects in the TIW group than in the QW and Q2W groups exceeded the Hb ceiling. Adverse events were similar across treatment groups and consistent with the morbidities of CKD patients.Conclusions: Administration of epoetin alfa at QW and Q2W intervals are potential alternatives to TIW dosing for the treatment of anemia in stage 3 to 4 CKD subjects.

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Section: Discussionmentioning

confidence: 99%

A Randomized Controlled Study of Weekly and Biweekly Dosing of Epoetin Alfa in CKD Patients With Anemia

Pèrgola

Gartenberg

et al. 2009

Clinical Journal of the American Society of Nephrology

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“…Hypertension was similar in Epo and darbepoetin arms in both trials (65,66). Not surprisingly, similar hypertensive effects in predialysis patients have been reported for pharmacologic administration of the newer ESA agents, pegylated Epo and hematide, which share Epo's mechanism of activating the Epo receptor (67,68).…”

Section: No Difference In Bp Response Between Darbepoetin or Epo In Pmentioning

confidence: 95%

Arterial Hypertension Induced by Erythropoietin and Erythropoiesis-Stimulating Agents (ESA)

Krapf¹,

Hulter²

2009

Clinical Journal of the American Society of Nephrology

161

118

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This review summarizes the evidence for a hypertensinogenic effect of Erythropoietin (Epo) in normal human subjects and predialysis, hemodialysis, and continuous ambulatory peritoneal dialysis (CAPD) patients. The possible mechanisms of Epo-induced hypertension are examined with in vivo animal and in vitro data, as well as pathophysiological human studies in both normal subjects and CKD patients. The evidence for a hypertensinogenic effect of erythropoiesis-stimulating agents (ESAs) in normal subjects, predialysis CKD, hemodialysis, and CAPD patients is compelling. Epo increases BP directly and notably independently of its erythropoietic effect and its effect on blood rheology. The potential for the development of future agents that might act as specific stimulators of erythropoiesis, devoid of direct hemodynamic side effects is underscored.

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“…Although darbepoetin alfa stimulates erythropoiesis in the same manner as endogenous erythropoietin, the increased carbohydrate content of the protein results in an approximately threefold longer serum half-life and greater in vivo biological activity, allowing for more convenient dosing intervals compared with rHuEPO [2]. Currently, darbepoetin alfa is approved for the treatment of anaemia secondary to chronic kidney disease [3][4][5] and anaemia associated with chemotherapy treatment of nonmyeloid cancers in adults [6,7]. In these patient populations, darbepoetin alfa effectively and safely maintains haemoglobin levels and, as shown in patients with chronic kidney disease [8,9], can be administered at dosing intervals of once monthly compared with more frequently dosed rHuEPO.…”

Section: Introductionmentioning

confidence: 99%

Population pharmacokinetics of darbepoetin alfa in healthy subjects

Agoram

Sutjandra

Sullivan

2006

Brit J Clinical Pharma

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AimTo develop and evaluate a population pharmacokinetic (PK) model of the long-acting erythropoiesis-stimulating protein, darbepoetin alfa in healthy subjects. MethodsPK profiles were obtained from 140 healthy subjects receiving single intravenous and/or single or multiple subcutaneous doses of darbepoetin alfa (0.75-8.0 µ g kg − 1 , or either 80 or 500 µ g). Data were analysed by a nonlinear mixed-effects modelling approach using NONMEM software. Influential covariates were identified by covariate analysis emphasizing parameter estimates and their confidence intervals, rather than stepwise hypothesis testing. The model was evaluated by comparing simulated profiles (obtained using the covariate model) to the observed profiles in a test dataset. ResultsThe population PK model, including first-order absorption, two-compartment disposition and first-order elimination, provided a good description of data. Modelling indicated that for a 70-kg human, the observed nearly twofold disproportionate doseexposure relationship at the 8.0 µ g kg − 1 -dose relative to the 0.75 µ g kg − 1 -dose may reflect changing relative bioavailability, which increased from ∼ 48% at 0.75 µ g kg − 1 to 78% at 8.0 µ g kg − 1 . The covariate analysis showed that increasing body weight may be related to increasing clearance and central compar tment volume, and that the absorption rate constant decreased with increasing age. The full covariate model performed adequately in a fixed-effects prediction test against an external dataset. ConclusionThe developed population PK model describes the inter-and intraindividual variability in darbepoetin alfa PK. The model is a suitable tool for predicting the PK response of darbepoetin alfa using clinically untested dosing regimens.

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Novel erythropoiesis stimulating protein for treatment of anemia in chronic renal insufficiency

Abstract: These results demonstrate that NESP safely and effectively corrects and maintains hemoglobin concentrations at a reduced dosing frequency relative to rHuEPO in patients with CRI, providing a potential benefit to patients and health care providers.

Cited by 174 publications

References 11 publications

A Randomized Controlled Study of Weekly and Biweekly Dosing of Epoetin Alfa in CKD Patients With Anemia

A Randomized Controlled Study of Weekly and Biweekly Dosing of Epoetin Alfa in CKD Patients With Anemia

Arterial Hypertension Induced by Erythropoietin and Erythropoiesis-Stimulating Agents (ESA)

Population pharmacokinetics of darbepoetin alfa in healthy subjects

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