Extended Administration Intervals Research Articles

A Prospective Study on Efficacy of Mircera for Treating Anemia Associated with Chronic Kidney Disease

Background: Chronic kidney disease (CKD) is a risk factor for end-stage renal failure and cardiovascular events. High incidence of anaemia is found in CKD stage 3 and 4. MIRCERA a continuous erythropoietin receptor activator is in development to provide anaemia correction and stable maintenance of haemoglobin (Hb) levels at extended administration intervals in patients with chronic kidney disease (CKD). This study examined its efficacy when administered up to once monthly in patients with CKD. Methodology: This study involved a prospective examination of haemoglobin levels in CKD patients by collecting and documentation the information of the patient including patient demographics, past medical history, medication history, and laboratory data. All enrolled patients were assessed for haemoglobin levels for every 4 weeks. Results: The haemoglobin levels after 24 weeks treatment with Mircera were found to be significantly high when compared with baseline haemoglobin levels in CKD patients who didn’t receive Mircera (P<0.0001). Conclusion: Mircera demonstrated improved efficacy in treating anemia in patients with CKD when given twice weekly for 24 weeks.

Differentiating Factors Between Erythropoiesis-Stimulating Agents: An Update to Selection for Anaemia of Chronic Kidney Disease

Erythropoiesis-stimulating agents (ESAs) have become a hallmark of anaemia therapy in patients with chronic kidney disease (CKD). Although different ESAs are available for the treatment of renal anaemia, each nephrologist should select a single ESA for an individual patient. Epoetin alfa and epoetin beta have been used 1-3 times weekly but extended-interval dosing up to every 4weeks is also effective in a substantial majority of CKD patients. However, the epoetin dose necessary to achieve or maintain target haemoglobin (Hb) levels increases substantially as the dosing interval increases. Subcutaneous administration of short-acting ESAs is more effective than the intravenous route of administration. Darbepoetin alfa and the continuous erythropoietin receptor activator (CERA) have been developed as a treatment for anaemia with extended administration intervals (every 2weeks and every 4weeks, respectively). Dose requirements for these long-acting ESAs are independent of the route of administration. Patents of short-acting ESAs have expired, which has opened the field for biosimilars. Epoetin biosimilars approved by the European Medicines Agency (EMA) or the US Food and Drug Administration (FDA) have been shown to have a comparable efficacy and safety profile to their originators. An alarming increase in pure red cell aplasia (PRCA) in Thailand with follow-on epoetins manufactured in Asia (but also those manufactured in Latin America) indicates that stringent country-specific approval and pharmacovigilance protocols for ESAs manufactured in non-North American and non-EU European countries are urgently needed. Two PRCA cases occurring with subcutaneous HX575 (one certain, one likely) indicate that chances of inducing a more immunogenic product are unpredictable, even with a biosimilar epoetin approved under the EMA biosimilar approval pathway. Phase III clinical trials with peginesatide, a pegylated synthetic peptide-based ESA without any homology to erythropoietin raised safety concerns in non-dialysis CKD patients but not in dialysis patients.

Pharmacokinetic and pharmacodynamic profiles of subcutaneous administration of continuous erythropoietin receptor activator in lung cancer patients with anemia induced by chemotherapy

Continuous erythropoietin receptor activator (C.E.R.A.) is an innovative erythropoiesis-stimulating agent with unique erythropoietin receptor activity and a prolonged half-life. C.E.R.A. is currently in development for the correction of anemia and stable hemoglobin (Hb) control at extended administration intervals in patients with cancer who are receiving chemotherapy. The purpose of this pharmacological study was to evaluate the pharmacokinetic (PK), pharmacodynamic (PD) and safety profiles of C.E.R.A. administered subcutaneously once every 3 weeks (Q3W) in lung cancer patients with anemia induced by chemotherapy. This open-label, multicenter study recruited 46 patients. Entry Hb levels were not more than 11.0 g/dl. Five dose levels of C.E.R.A. (2.1, 4.2, 6.3, 9 and 12 μg/kg) were tested in sequential cohorts of 8-11 patients for 12 weeks. The mean values for C.E.R.A half-life ranged from 143 to 247 h. The maximum serum concentration (C(max)) following the first administration of C.E.R.A. increased in proportion to the dose. The increase of Hb levels occurred in a dose-dependent manner. No serious adverse events reported as being related to C.E.R.A. were observed during the study period. Thrombovascular events were not observed in any patient. Anti-C.E.R.A antibodies were not detected in any patient. Thus, this pharmacological study confirmed the long half-life of C.E.R.A., thereby supporting subcutaneous administration of C.E.R.A. at the Q3W interval. PK and PD parameters demonstrated dose-proportionality over the range of doses tested in this study. Additionally, C.E.R.A. was generally well tolerated.

Extended administration of erythropoiesis-stimulating agents for optimising the management of renal anaemia: what is the evidence?

Erythropoiesis-stimulating agents (ESAs) have transformed the management of anaemia in patients with chronic kidney disease (CKD), reducing transfusion requirements and leading to improved quality of life. However, effective anaemia management with current ESAs is labour-intensive and time-consuming. Approaches are required to simplify anaemia management and reduce the burden on healthcare systems. There is increasing interest in extending the administration interval of ESAs. This would result in considerable time-savings, reducing the workload of healthcare providers and potentially reducing healthcare system costs. Time saved could be utilised in improving other aspects of patient care, such as implementation of guidelines, or treating more patients. Potential benefits of extended administration intervals for patients include a less demanding regimen and fewer injections, which could lead to improved adherence to treatment. This article reviews studies of the efficacy of current ESAs in maintaining stable haemoglobin (Hb) levels when used at extended administration intervals of up to once monthly. Patients who are already stable on more frequent ESA therapy and who respond well to treatment may be able to maintain stable Hb with extended dosing regimens with established ESAs. However, few patients with CKD currently receive ESAs once-monthly in clinical practice. New agents with long half-lives offer the potential for extended dosing regimens in all patients with CKD.

Efficacy of Intravenous Methoxy Polyethylene Glycol-Epoetin Beta Administered Every 2 Weeks Compared With Epoetin Administered 3 Times Weekly in Patients Treated by Hemodialysis or Peritoneal Dialysis: A Randomized Trial

C.E.R.A. (methoxy polyethylene glycol-epoetin beta), a continuous erythropoietin receptor activator, was developed to provide stable control of hemoglobin (Hb) levels at extended administration intervals in patients with chronic kidney disease. We examined its efficacy for Hb level correction when administered once every 2 weeks in erythropoiesis-stimulating agent-naive dialysis patients. Open-label, multicenter, randomized, parallel-group, phase 3 study. Dialysis patients (age >or= 18 years). Patients (n = 181) were randomly assigned (3:1) to receive intravenous C.E.R.A. once every 2 weeks or epoetin 3 times weekly. The primary end point was Hb level response rate (increase in Hb level >or= 1 g/dL [10 g/L] versus baseline and Hb level >or= 11 g/dL [110 g/L] without blood transfusion during the 24-week correction period) in the intent-to-treat population. Hb response rates (intent-to-treat population) were 93.3% with C.E.R.A. and 91.3% with epoetin. Similar results were found in the per-protocol population. Peak mean Hb levels were 12.28 +/- 1.13 (SD) g/dL (122.8 +/- 11.3 g/L) with C.E.R.A. and 12.19 +/- 1.24 g/dL (121.9 +/- 12.4 g/L) with epoetin. Mean change in Hb levels from baseline to the end of the correction period were 2.70 +/- 1.45 g/dL (27 +/- 14.5 g/L) with C.E.R.A. and 2.56 +/- 1.31 g/dL (25.6 +/- 13.1 g/L) with epoetin. Both treatments were generally well tolerated. Open-label study design, 3:1 randomization, limited peritoneal dialysis population, descriptive statistics, and lack of formal prespecified comparison to epoetin. Intravenous C.E.R.A. once every 2 weeks may be as safe and effective as 3-times-weekly epoetin for correcting anemia in dialysis patients. These results show the utility of intravenous C.E.R.A. administered once every 2 weeks in erythropoiesis-stimulating agent-naive dialysis patients.

ADDRESSING THE CHALLENGES OF RENAL ANAEMIA: HOW NURSES CAN MAKE A DIFFERENCE

Nephrology nurses play a central and wide-ranging role in renal care. However, they have inadequate time to manage their responsibilities as patient volume increases due to earlier diagnosis and improved survival, and patient care becomes more complex. The challenge to achieve and maintain target haemoglobin levels with current agents compounds nursing workload. Early recognition and treatment of anaemia, a multidisciplinary approach and patient management algorithms can improve outcomes and nursing time utilisation. Innovative erythropoietic agents produce stable haemoglobin levels at extended administration intervals, offering time-savings. Such initiatives may allow nurses more time to focus on other aspects of patient care.

Erratum

International Journal of Clinical PracticeVolume 61, Issue 10 p. 1776-1777 Free Access Erratum This article corrects the following: Continuous Erythropoietin Receptor Activator (C.E.R.A.) administered at extended administration intervals corrects anaemia in patients with chronic kidney disease on dialysis: a randomised, multicentre, multiple-dose, phase II study A. L. M. DE FRANCISCO, W. SULOWICZ, M. KLINGER, S. NIEMCZYK, V. VARGEMEZIS, F. METIVIER, F. C. DOUGHERTY, D. OGUEY, , Volume 60Issue 12International Journal of Clinical Practice pages: 1687-1696 First Published online: November 10, 2006 First published: 14 September 2007 https://doi.org/10.1111/j.1742-1241.2007.01572.xCitations: 1AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Original article ‘Continuous Erythropoietin Receptor Activator (C.E.R.A.) administered at extended administration intervals corrects anaemia in patients with chronic kidney disease on dialysis: a randomized, multicentre, multiple-dose, phase II study’. Int J Clin Pract 2006; 60: 1687–96. We would like to apologise for the wrong country name being published in the Acknowledgements section for Dr C-C Huang and Dr J-J Huang in the above article. The text should read as follows: The authors would like to thank the DSMB members and the following investigators for their involvement in the BA16260 study; by country: Dr A. Disney (Australia), Dr C. Hawley (Australia), Dr C-C Huang (Taiwan), Dr J-J Huang (Taiwan), Prof. J-M Chalopin (France), Prof. J. Chanard (France), Prof. C. Combe (France), Dr C. Granolleras (France), Prof. T. Hannedouche (France), Prof. M. Labeeuw (France), Prof. G. Schultze (Germany), Dr C. Iatrou (Greece), Prof. K.C. Siamopoulos (Greece), Dr K. Bidas (Poland), Prof. S. Czekalski (Poland), Prof. B. Rutkowski (Poland), Dr M. Arias (Spain) and Dr A. Bajo Rubio (Spain). Reference 1 De Francisco ALM, Sulowicz W, Klinger M, Niemczyk S, Vargemezis V, Metivier F, Dougherty FC, Oguey D, On Behalf of The BA16260 Study Investigators. Continuous Erythropoietin Receptor Activator (C.E.R.A.) administered at extended administration intervals corrects anaemia in patients with chronic kidney disease on dialysis: a randomized, multicentre, multiple-dose, phase II study. Int J Clin Pract 2006; 60: 1687– 96. Citing Literature Volume61, Issue10October 2007Pages 1776-1777 ReferencesRelatedInformation

RENAL ANAEMIA: RECENT DEVELOPMENTS AND FUTURE DIRECTIONS FOR IMPROVED MANAGEMENT

The global burden of chronic kidney disease (CKD) and associated anaemia is substantial. With the increasing numbers of patients that are likely to be affected in the future, approaches are required to improve anaemia management without increasing the workload of renal units. Advocating early treatment may improve patient outcomes and nurses are in an ideal position to identify and manage anaemia at an early stage in patients with CKD. In addition, adopting a multidisciplinary approach, alongside nephrologists, diabetologists, cardiologists, social workers, nutritionists and pharmacists, may allow nurses to detect and treat anaemia earlier in patients with CKD. Maintaining awareness of factors associated with decreased erythropoiesis-stimulating agents (ESAs) efficacy (e.g. iron deficiency or poor nutritional status) is also important. To reduce the burden on healthcare providers, anaemia management could be simplified by extending the administration interval of ESAs. Recent studies have explored the clinical efficacy of administration of currently available agents at intervals of up to once monthly in highly selected, stable patients. The use of an ESA that can control anaemia while maintaining haemoglobin levels within guideline ranges with extended administration intervals in all patients without the need for additional screening or stepwise dose adjustments with attendant monitoring may help improve patient care while reducing the workload of healthcare providers.

Once-Monthly Subcutaneous C.E.R.A. Maintains Stable Hemoglobin Control in Patients with Chronic Kidney Disease on Dialysis and Converted Directly from Epoetin One to Three Times Weekly

C.E.R.A., a continuous erythropoietin receptor activator, is in development to provide anemia correction and stable maintenance of hemoglobin (Hb) levels at extended administration intervals in patients with chronic kidney disease (CKD). This study examined its efficacy and safety when administered up to once monthly in patients who have CKD and are on dialysis and randomly convert directly from epoetin alpha or beta one to three times weekly. In this three-arm, comparator-controlled, open-label, randomized, parallel-group, Phase III study, 572 dialysis patients (> or =18 yr) who were receiving stable subcutaneous epoetin one to three times weekly were randomly assigned (1:1:1) to continue epoetin or to receive subcutaneous C.E.R.A. once monthly or twice monthly for 52 wk. Dosage was adjusted to maintain Hb +/-1.0 g/dl of baseline level. Primary end point was mean change in Hb level between baseline and the evaluation period (weeks 29 to 36). Mean Hb levels during the evaluation period were similar between groups (once-monthly C.E.R.A. 11.5 g/dl; twice-monthly C.E.R.A. 11.7 g/dl; epoetin 11.5 g/dl). The difference between C.E.R.A. and epoetin in mean change (97.5% confidence interval) in Hb concentration between baseline and evaluation was -0.022 g/dl (-0.262 to 0.217) for once monthly and 0.141 g/dl (-0.098 to 0.380) for twice monthly. Analysis demonstrated that C.E.R.A. was as effective as epoetin in maintaining Hb and was well tolerated. Subcutaneous C.E.R.A. once or twice monthly successfully maintained tight and stable Hb levels in patients who were on dialysis and randomly converted directly from epoetin one to three times weekly.

Effect of a continuous erythropoietin receptor activator (C.E.R.A.) on stable haemoglobin in patients with CKD on dialysis: once monthly administration

ABSTRACTAims: This Phase II study aimed to determine the optimal dose and administration schedule of continuous erythropoietin receptor activator (C.E.R.A.) given subcutaneously (SC) in patients receiving dialysis converting directly from SC epoetin therapy 1–3 times/week. An extension phase examined long-term safety and efficacy.Methods: Patients were assigned to one of three C.E.R.A. dose groups determined by multiplying the previous weekly dose of epoetin by one of three ratios (0.4/150, 0.8/150, 1.2/150 for groups A, B and C, respectively). Within each group, patients were randomized to once weekly (QW), once every 3 weeks (Q3W) and once monthly (Q4W) schedules. Dose adjustments were not permitted for the first 6 weeks. The core study period was 19 weeks (21 weeks in the Q4W cohorts). Patients could enter a 12‑month extension period at the same schedule, aiming to maintain haemoglobin (Hb) at 11–12 g/dL.Results: 137 patients entered the core period, and 62 continued into the extension period. A dose-dependent relationship was seen in the primary efficacy variable, change in Hb standardized to a 6 week period ( p < 0.0001), but effect was independent of schedule. Hb levels were maintained throughout the study, with few dose changes. C.E.R.A. was generally well tolerated and the most frequent adverse event was hypotension.Conclusion: The results suggest that SC C.E.R.A. at up to once monthly intervals provides stable maintenance of Hb levels in dialysis patients converting directly from epoetin 1–3 times/week. Achieving tight Hb control with few dose adjustments at extended administration intervals may offer health benefits and improvements in resource management.Trial registration: ClinicalTrials.gov identifier: NCT00364832.

Consumption of C.E.R.A. and Epoetin Beta in a Cellular Assay: UT-7 Consumption Model.

Continuous Erythropoietin Receptor Activator (C.E.R.A.), an innovative erythropoietic agent with unique receptor activity, is currently in development to provide correction of anemia and stable maintenance of hemoglobin (Hb) levels at extended administration intervals up to once monthly in patients with all stages of chronic kidney disease, and is also in development for the treatment of chemotherapy-induced anemia. C.E.R.A. has an equivalent half-life in humans of approximately 130 h following subcutaneous or intravenous administration. Clearance of erythropoietic agents may occur by binding, internalization and degradation in receptor bearing cells in the bone marrow. A functional assay was developed to evaluate the consumption of C.E.R.A. and epoetin beta in a UT-7 cellular system (a human acute myeloid leukemia cell line whose growth is dependent on the presence erythropoietic and other growth factors). UT-7 cells were incubated in the presence of C.E.R.A. (1000 pM) or epoetin beta (100 pM) for 72, 96 or 120 h. The cell supernatants were then harvested and the amounts of remaining growth factor were determined by a validated erythropoietin ELISA. As controls, the growth factors were incubated for the same times in medium only. Five independent identical experiments were conducted for each compound. Mean percentages of C.E.R.A. and epoetin beta were calculated relative to the control values (set at 100%). C.E.R.A. 1000 pM and epoetin beta 100 pM were shown to be equipotent, stimulating the proliferation of UT-7 cells to the same degree. There was a highly significant difference (P=1.9×10−9) between C.E.R.A. and epoetin beta for the time course of concentrations relative to controls. For epoetin beta 100 pM, the relative concentration decreased significantly over time, while for C.E.R.A. 1000 pM no statistically significant changes were observed. Thus, C.E.R.A. was still present in the culture supernatant at close to 100% after 4–5 days' incubation, while the epoetin beta concentration had declined to approximately 20%. In conclusion, at the end of the incubation time the C.E.R.A. concentration was still sufficient to maintain the initial level of cell stimulation. However, at the end of the 96 h incubation the epoetin beta concentration dropped to a level that was insufficient to produce further stimulation. The UT-7 consumption model thus emulates the in vivo situation in humans with regard to receptor mediated elimination of the compounds and stimulation of erythroid progenitors.This study provides further evidence that C.E.R.A. interacts differently with the erythropoietin receptor relative to epoetin beta. Preclinical studies have shown that these properties translate into more continuous stimulation of erythropoiesis in vivo compared with epoetin beta and Phase III data indicate that C.E.R.A. allows predictable Hb maintenance in direct conversion from more frequently dosed agents.

C.E.R.A. Acts Differently at the Erythropoietin (EPO) Receptor Compared with Epoetin Beta: UT-7 and CD34+ Cell Stimulation Assays.

Continuous Erythropoietin Receptor Activator (C.E.R.A.), an innovative erythropoietic agent with unique receptor activity, is currently in development to provide correction of anemia and stable maintenance of hemoglobin (Hb) levels at extended administration intervals up to once monthly in patients with all stages of chronic kidney disease (CKD), and is also in development for the treatment of chemotherapy-induced anemia. In vitro studies show that C.E.R.A. has a 45-fold lower affinity for the EPO receptor than epoetin beta, due mainly to a reduced association rate. To further investigate the in vitro activity of C.E.R.A., two cell stimulation studies were undertaken. Study 1 evaluated an assay for the analysis of the molecular mechanism of C.E.R.A.- and epoetin beta-mediated cell activation. UT-7 cells were activated with C.E.R.A. or epoetin beta for 72 h or 96 h, followed by WST (tetrazolium salt) staining and spectrophotometric detection. UT-7 is a human myeloid leukemia cell line expressing the EPO receptor, and has growth dependency on EPO if no other growth factors are present. Results showed that the EC50 (concentration giving half maximal stimulation) value was approximately 10-fold higher for C.E.R.A. (range 300–400 pM) than for epoetin beta (30–60 pM). Maximal activation of UT-7 cells was achieved at C.E.R.A. 1000–2000 pM and epoetin beta 100–200 pM, but the maximal stimulation of cells was similar for both agents. Study 2 investigated the effects of C.E.R.A. and epoetin beta on stimulation of the proliferation and differentiation of human CD34+ cells. Human CD34+ stem cells from cord blood and bone marrow were cultivated with C.E.R.A. or epoetin beta for 8–14 days. After labeling, using fluorescence-tagged antibodies to proteins specific for erythroid cells (glycophorin A) and other blood cell types (CD13, CD14, CD16, CD41, CD42b, and CD61), cells were analyzed using three-color flow cytometry with a FACScan instrument (Becton Dickinson, CA). The maximal number of glycophorin A positive cells at plateau phase was used for EC50 calculation. Following stimulation of CD34+ cells, glycophorin A+ cells increased to a similar level with C.E.R.A. and epoetin beta. This stimulation was specific for erythroid precursors since the differentiation of white blood cells and megakaryocytes was not affected by C.E.R.A. or epoetin beta. Notably, mean EC50 values were 43.4-fold higher with C.E.R.A. (2.807 nM) than with epoetin beta (0.076 nM). In conclusion, C.E.R.A. and epoetin beta activate UT-7 cells and induce differentiation and expansion of CD34+ cells. These studies provide further evidence that C.E.R.A. has different EPO receptor binding properties compared with epoetin beta and demonstrate its specificity for the red blood cell line. Preclinical studies have shown that these properties translate into more continuous stimulation of erythropoiesis in vivo compared with epoetin beta and Phase III data indicate that C.E.R.A. achieved and maintained stable Hb levels in all patients with CKD.

Continuous Erythropoietin Receptor Activator (C.E.R.A.) administered at extended administration intervals corrects anaemia in patients with chronic kidney disease on dialysis: a randomised, multicentre, multiple-dose, phase II study

This dose-finding, open-label study examined the potential of subcutaneous Continuous Erythropoietin Receptor Activator (C.E.R.A.) to correct anaemia at extended administration intervals in 61 erythropoiesis-stimulating agent-naïve patients with chronic kidney disease (CKD) on dialysis. After a 4-week run-in, patients were randomised to C.E.R.A. 0.15, 0.30 and 0.45 microg/kg/week. Within these dose groups, patients were further randomised to once weekly, once every 2 weeks or once every 3 weeks treatment. Mean changes in haemoglobin (Hb) increased with increasing C.E.R.A. dose during a period of 6 weeks where no dose adjustments were permitted. The effect was independent of administration schedule. Erythropoietic responses were sustained until the end of the study (12 weeks) in all groups. In total, 90% of patients in the 0.30 microg/kg/week group and 79% in the 0.45 microg/kg/week group responded to treatment (Hb increase > or =1.0 g/dl), compared with 72% in the 0.15 microg/kg/week group. Faster median response time was associated with increasing dose (51, 38 and 31 days, respectively) and response was unrelated to administration frequency. C.E.R.A. was generally well tolerated. Our results suggest that 0.60 microg/kg twice monthly would be a suitable starting dose of C.E.R.A. for the initiation of anaemia correction in patients with CKD on dialysis. Phase III studies will confirm the feasibility of using C.E.R.A. at extended administration intervals in patients with CKD and anaemia.

Renal anaemia: Recent developments, innovative approaches and future directions for improved management (Review Article)

The morbidity, mortality and economic burden of chronic kidney disease (CKD) and associated anaemia are substantial. With the increasing numbers of patients who are likely to be affected in the future, approaches are required to improve anaemia management without increasing the burden on health-care professionals. A multidisciplinary approach to treatment, where early initiation of erythropoiesis-stimulating agents (ESA) is encouraged, may improve patient outcomes. Recent studies also suggest that the early use of iron therapy in patients with CKD not on dialysis may be associated with beneficial effects on haemoglobin levels. Another strategy to reduce the burden on health-care providers is to simplify anaemia management by extending the administration interval of ESA. Indeed, recent studies have explored the efficacy of extending the administration interval of ESA in clinical practice in CKD patients on dialysis and not on dialysis. The ability to maintain haemoglobin levels within guideline ranges at extended administration intervals may improve patient care and reduce the workload of health-care providers.

Pharmacokinetics and Pharmacodynamics of Intravenous and Subcutaneous Continuous Erythropoietin Receptor Activator (C.E.R.A.) in Patients with Chronic Kidney Disease

Continuous Erythropoietin Receptor Activator (C.E.R.A.) is a new agent that is in development for the treatment of anemia with extended administration intervals in patients who have chronic kidney disease (CKD), both those on and those not on dialysis. This was an open-label, randomized, multicenter, two-period, crossover study in erythropoiesis-stimulating agentnaïve patients who had CKD and anemia and were receiving peritoneal dialysis. After a 1-wk run-in period, 16 patients were randomly assigned to receive a single administration of intravenous C.E.R.A. 0.4 microg/kg (n = 8) or subcutaneous C.E.R.A. 0.8 microg/kg (n = 8). Six weeks after the first administration of C.E.R.A. (4-wk assessment, 2-wk washout), the route of administration was switched so that all patients received single administrations of both intravenous C.E.R.A. 0.4 microg/kg and subcutaneous C.E.R.A. 0.8 microg/kg. C.E.R.A. had a prolonged and comparable half-life after intravenous (mean 134 h) and subcutaneous (mean 139 h) administration. Reticulocyte counts peaked at a median of 8 d after intravenous and subcutaneous administration with no difference in the time course between administration routes. This resulted in similar mean values for the area under the reticulocyte count-time curve (1191 x 10(9) and 1193 x 10(9).d per L, respectively) and the maximum absolute increase in reticulocyte counts (36 x 10(9) and 41 x 10(9)/L, respectively). C.E.R.A. has a prolonged and comparable half-life after intravenous or subcutaneous injection, suggesting that extended administration intervals may be feasible in patients with CKD.