ABSTRACT
Current markers of iron deficiency (ID), such as ferritin and hemoglobin, have shortcomings, and hepcidin and erythroferrone (ERFE) could be of clinical relevance in relation to early assessment of ID. Here, we evaluate whether exposure to altitude-induced hypoxia (2,320 m) alone, or in combination with recombinant human erythropoietin (rHuEPO) treatment, affects hepcidin and ERFE levels before alterations in routine ID biomarkers and stress erythropoiesis manifest. Two interventions were completed, each comprising a 4-wk baseline, a 4-wk intervention at either sea level or altitude, and a 4-wk follow-up. Participants (n = 39) were randomly assigned to 20 IU·kg body wt-1 rHuEPO or placebo injections every second day for 3 wk during the two intervention periods. Venous blood was collected weekly. Altitude increased ERFE (P ≤ 0.001) with no changes in hepcidin or routine iron biomarkers, making ERFE of clinical relevance as an early marker of moderate hypoxia. rHuEPO treatment at sea level induced a similar pattern of changes in ERFE (P < 0.05) and hepcidin levels (P < 0.05), demonstrating the impact of accelerated erythropoiesis and not of other hypoxia-induced mechanisms. Compared with altitude alone, concurrent rHuEPO treatment and altitude exposure induced additive changes in hepcidin (P < 0.05) and ERFE (P ≤ 0.001) parallel with increases in hematocrit (P < 0.001), demonstrating a relevant range of both hepcidin and ERFE. A poor but significant correlation between hepcidin and ERFE was found (R2 = 0.13, P < 0.001). The findings demonstrate that hepcidin and ERFE are more rapid biomarkers of changes in iron demands than routine iron markers. Finally, ERFE and hepcidin may be sensitive markers in an antidoping context.
Subject(s)
Altitude Sickness/blood , Altitude , Epoetin Alfa/administration & dosage , Erythropoiesis/drug effects , Hematinics/administration & dosage , Hepcidins/blood , Iron/blood , Peptide Hormones/blood , Altitude Sickness/diagnosis , Biomarkers/blood , Denmark , Double-Blind Method , Female , Homeostasis , Humans , Injections, Intravenous , Male , Recombinant Proteins/administration & dosage , Spain , Time FactorsABSTRACT
We investigated whether immature reticulocyte fraction (IRF) and immature reticulocytes to red blood cells ratio (IR/RBC) are sensitive biomarkers for low-dose recombinant human erythropoietin (rhEpo) treatment at sea level (SL) and moderate altitude (AL) and whether multi (FACS) or single (Sysmex-XN) fluorescence flow cytometry is superior for IRF and IR/RBC determination. Thirty-nine participants completed two interventions, each containing a 4-week baseline, a 4-week SL or AL (2,230 m) exposure, and a 4-week follow-up. During exposure, rhEpo (20 IU kg-1 ) or placebo (PLA) was injected at SL (SLrhEpo , n = 25, SLPLA n = 9) and AL (ALrhEpo , n = 12, ALPLA n = 27) every second day for 3 weeks. Venous blood was collected weekly. Sysmex measurements revealed that IRF and IR/RBC were up to ~70% (P < 0.01) and ~190% (P < 0.001) higher in SLrhEpo than SLPLA during treatment and up to ~45% (P < 0.001) and ~55% (P < 0.01) lower post-treatment, respectively. Compared with ALPLA , IRF and IR/RBC were up to ~20% (P < 0.05) and ~45% (P < 0.001) lower post-treatment in SLrhEpo , respectively. In ALrhEpo , IRF and IR/RBC were up to ~40% (P < 0.05) and ~110% (P < 0.001) higher during treatment and up to ~25% (P < 0.05) and ~40% (P < 0.05) lower post-treatment, respectively, compared with ALPLA . Calculated thresholds provided ~90% sensitivity for both biomarkers at SL and 33% (IRF) and 66% (IR/RBC) at AL. Specificity was >99%. Single-fluorescence flow cytometry coefficient of variation was >twofold higher at baseline (P < 0.001) and provided larger or similar changes compared to multi-fluorescence, albeit with smaller precision. In conclusion, IRF and IR/RBC were sensitive and specific biomarkers for low-dose rhEpo misuse at SL and AL.
Subject(s)
Altitude , Epoetin Alfa/pharmacology , Hematinics/pharmacology , Reticulocytes/drug effects , Adult , Biomarkers/metabolism , Double-Blind Method , Epoetin Alfa/administration & dosage , Erythrocyte Count , Erythrocytes/cytology , Female , Flow Cytometry , Follow-Up Studies , Hematinics/administration & dosage , Humans , Male , Reticulocyte Count , Reticulocytes/cytology , Young AdultABSTRACT
PURPOSE: Impaired response to erythropoietin underlies ineffective erythropoiesis and anemia in myelodysplastic syndromes (MDS). We investigated whether treatment with lenalidomide (LEN), which augments erythropoietin receptor signaling in vitro, can restore and improve hemoglobin response to epoetin (EPO) alfa in patients with lower-risk, non-del(5q) MDS who have anemia that is refractory to or have low probability of benefit from treatment with recombinant erythropoietin. METHODS: In a phase III, US intergroup trial, we randomly assigned patients to receive either LEN and EPO alfa or LEN alone following stratification by serum erythropoietin concentration and prior erythropoietin treatment. RESULTS: A total of 195 evaluable patients were randomly assigned: 99 patients to the LEN-EPO alfa cohort and 96 to LEN alone. After four cycles of treatment, the primary end point of major erythroid response (MER) was significantly higher (28.3%) with the combination compared with LEN alone (11.5%) (P = .004). Among 136 patients who completed 16 weeks of study treatment, 38.9% and 15.6% achieved MER, respectively (P = .004). Additionally, minor erythroid response was achieved in 18.2% and 20.8% of patients, for an overall erythroid response rate of 46.5% versus 32.3%. Among LEN nonresponders, 38 crossed over to the addition of EPO alfa with 10 patients (26.3%) achieving a MER. Responses to the combined treatment were highly durable with a median MER duration of 23.8 months compared with 13 months with LEN alone. CONCLUSION: LEN restores sensitivity to recombinant erythropoietin in growth factor-insensitive, lower-risk, non-del(5q) MDS, to yield a significantly higher rate and duration of MER compared with LEN alone (funded by the National Cancer Institute; E2905 ClinicalTrials.gov identifier: NCT02048813).
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Drug Resistance, Neoplasm/drug effects , Myelodysplastic Syndromes/drug therapy , Neoplasm Recurrence, Local/drug therapy , Recombinant Proteins/pharmacology , Aged , Aged, 80 and over , Epoetin Alfa/administration & dosage , Female , Follow-Up Studies , Humans , Lenalidomide/administration & dosage , Male , Middle Aged , Myelodysplastic Syndromes/pathology , Neoplasm Recurrence, Local/pathology , Prognosis , Survival RateABSTRACT
Introduction: Erythropoietin stimulating agents (ESAs) have been established both to correct anemia and provide the clinical benefits of increased exercise capacity, reduced transfusion requirements, and improved quality of life. An increase in physician and patient adoption of biosimilars, as well as changes to healthcare reimbursement policies, have driven market competitors to innovate and expand the range of biosimilar products. While erythropoietin biosimilars have been approved by the EMA since 2007, the FDA's approval of epoetin alfa-epbx in 2018 marks the first erythropoietin biosimilar approved in the United States. Areas covered: In this article, we critically review the biology, clinical use, manufacturing, safety, and efficacy of ESAs and erythropoietin biosimilars. We then review the regulatory framework and potential impact on healthcare costs offered by erythropoietin biosimilars. Expert opinion: Due to the complex nature of manufacturing large-molecule biologics, it is important to recognize the challenges to quality assurance and overall safety posed by the introduction of biosimilars, which undergo much more limited clinical testing than their reference biologic product before coming to market. With many biologic therapies nearing patent expiration, biosimilars will become increasingly common in clinical practice. Ensuring patient safety with these products will require increased post-marketing surveillance and awareness from prescribers.
Subject(s)
Biosimilar Pharmaceuticals/administration & dosage , Epoetin Alfa/administration & dosage , Hematinics/administration & dosage , Anemia/drug therapy , Biosimilar Pharmaceuticals/adverse effects , Drug Approval , Epoetin Alfa/adverse effects , Hematinics/adverse effects , Humans , Quality of Life , United StatesABSTRACT
The ability to control dosage regimens of erythropoiesis-stimulating agents (ESAs) to maintain a desired hemoglobin (HGB) target is still elusive. We utilized a Bayesian approach and informative priors to characterize HGB profiles, using simulated drug concentrations, in patients with end-stage renal disease receiving maintenance doses of epoetin alfa. We also demonstrated an adaptive Bayesian method, applied to individual patients, to improve the accuracy of HGB predictions over time. The results showed that sparse HGB data from daily clinical practice were characterized successfully. The adaptive Bayesian method effectively improved the accuracy of HGB predictions by updating the individual model with new data accounting for within-subject changes over time. The Bayesian approach presented leverages existing knowledge of the model parameters and has a potential utility in clinical practice to individualize dosage regimens of epoetin alfa and ESAs to achieve target HGB. Further studies are warranted to develop an application for practical use.
Subject(s)
Anemia/drug therapy , Epoetin Alfa/pharmacology , Hematinics/pharmacology , Hemoglobins/drug effects , Kidney Failure, Chronic/therapy , Adult , Aged , Aged, 80 and over , Algorithms , Anemia/etiology , Anemia/prevention & control , Bayes Theorem , Dose-Response Relationship, Drug , Drug Development/methods , Drug Discovery/methods , Epoetin Alfa/administration & dosage , Epoetin Alfa/therapeutic use , Female , Hematinics/administration & dosage , Hematinics/therapeutic use , Hemoglobins/analysis , Humans , Kidney Failure, Chronic/blood , Kidney Failure, Chronic/complications , Male , Middle Aged , Prospective Studies , Retrospective StudiesABSTRACT
BACKGROUND: Hematologic toxicities are one of the greatest challenges in adjuvant chemotherapy for breast cancer. This analysis of the ADEBAR trial aims to evaluate application and effect of granulocyte colony-stimulating factor (G-CSF) and epoetin alfa (EPO) on hematologic parameters and fatigue in patients with breast cancer during chemotherapy. PATIENTS AND METHODS: In the ADEBAR trial, 1493 patients with node-positive primary breast cancer were randomized to either 6 × 5-fluorouracil, epirubicin, and cyclophosphamide (FEC120) or 4 × epirubicin and cyclophosphamide followed by 4 × docetaxel (EC-DOC). Co-medication with G-CSF or EPO was applied to treat chemotherapy-induced leukopenia or anemia. Fatigue was assessed at baseline and after one-half of the chemotherapy. RESULTS: In total, 899 patients could be included in the analysis. There was no evidence for an association between leucocyte or hemoglobin levels and application of G-CSF and EPO in the preceding cycle, respectively. Hemoglobin levels (B = -0.41; P < .001) were affected by treatment regimen. Fatigue during chemotherapy was mostly affected by the level of fatigue before the start of chemotherapy (B = 0.41; P < .001). Patients with G-CSF application in the preceding cycle showed an increased fatigue score (B = 5.43; P = .02). CONCLUSION: We showed that fatigue during adjuvant chemotherapy was mostly affected by the level of fatigue present before the start of chemotherapy. This result suggests that the level of fatigue before the start of treatment should be included as an important factor when deciding on type and toxicity of chemotherapy in early breast cancer.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/adverse effects , Breast Neoplasms/therapy , Epoetin Alfa/administration & dosage , Fatigue/epidemiology , Granulocyte Colony-Stimulating Factor/administration & dosage , Adolescent , Adult , Aged , Anemia/chemically induced , Anemia/diagnosis , Anemia/epidemiology , Anemia/prevention & control , Breast Neoplasms/blood , Breast Neoplasms/complications , Breast Neoplasms/diagnosis , Chemotherapy, Adjuvant/adverse effects , Chemotherapy, Adjuvant/methods , Fatigue/chemically induced , Fatigue/diagnosis , Fatigue/prevention & control , Female , Hemoglobins/analysis , Humans , Leukocyte Count , Leukopenia/chemically induced , Leukopenia/diagnosis , Leukopenia/epidemiology , Leukopenia/prevention & control , Middle Aged , Neoplasm Staging , Prospective Studies , Quality of Life , Severity of Illness Index , Young AdultABSTRACT
Objectives Recombinant human erythropoietin (rhEPO) has been shown to effectively and safely prevent the anemia of prematurity and to reduce the transfusion need in very low birth weight (VLBW) infants and has been licensed for this indication in Europe in 1997. The objective of the study was to obtain information on the use or non-use of rhEPO in neonatal units in Germany and other European countries. Methods Anonymized 14-questions web-based questionnaire. Results Seventy-nine questionnaires from Germany and 63 questionnaires from other 15 European countries were completed. Of the responders, 39% indicated to use rhEPO routinely or occasionally in VLBW infants, whereas 61% responded to never use rhEPO in this population. The major reasons given for non-use were lack of recommendation in national guidelines (69%) and/or doubt about efficacy of rhEPO to reduce transfusion need (53%). Twenty-seven percent of the responders indicated to use rhEPO for neonates with birth weights above 1,500 g. Neuroprotection in VLBW infants (26%) and hypoxic ischemic encephalopathy in term neonates (27%) were given as indications for off label use of rhEPO. Conclusions This survey indicates that rhEPO is used for the anemia of prematurity as licensed in less than half of neonatal units in Germany and other European countries. On the other hand it seems to be used off label in neonates for neuroprotection in a considerable number of units although there is no final evidence on its neuroprotective effects.
Subject(s)
Anemia, Neonatal , Drug Utilization Review , Epoetin Alfa/administration & dosage , Hypoxia-Ischemia, Brain , Anemia, Neonatal/etiology , Anemia, Neonatal/prevention & control , Drug Utilization Review/methods , Drug Utilization Review/statistics & numerical data , Europe/epidemiology , Female , Health Care Surveys , Hematinics/administration & dosage , Humans , Hypoxia-Ischemia, Brain/etiology , Hypoxia-Ischemia, Brain/therapy , Infant Health/statistics & numerical data , Infant, Newborn , Infant, Premature/blood , Infant, Very Low Birth Weight/blood , Male , Neuroprotective Agents/administration & dosageABSTRACT
Growth hormone (GH), an endogenous peptide regulating anabolism and lipolysis in humans, is known to be abused by athletes to improve their performance. Despite the development of two distinct screening methods, few positive cases have been reported by the antidoping authorities, probably due to the quick turnover of GH and the masking effects of age, ethnicity, and sex. Apart from growth regulation, GH is known to affect several metabolic pathways in humans including ketosis, amino-acid uptake, and protein breakdown. It is reasonable to imagine observing its markers of effects through the leading tool on metabolism study, metabolomics. In this proof-of-concept study, a cohort of well-trained volunteers was split in two equal groups and administered with micro-doses of EPO or EPO + GH every second day for 2 weeks. Urine and plasma samples were collected before, during, and after treatment and analyzed using metabolomics and lipidomics approaches. The results show that, by applying a direct discriminant analysis on the treated groups, it is possible to distinguish the treatments, and to use this difference to classify them correctly. High intragroup variability is observed, due to the subject-specific effect of the hormones. Through time 0 centering the data, a longitudinally tracking of the group was performed and a higher difference was observed between the groups, including a perfect classification of the samples before and after the treatments.
Subject(s)
Epoetin Alfa/analysis , Human Growth Hormone/analysis , Metabolomics/methods , Adolescent , Adult , Athletes , Cohort Studies , Epoetin Alfa/administration & dosage , Epoetin Alfa/pharmacokinetics , Human Growth Hormone/administration & dosage , Human Growth Hormone/pharmacokinetics , Humans , Lipidomics/methods , Male , Proof of Concept Study , Young AdultABSTRACT
FUNDAMENTO: Determinar la adherencia al tratamiento con agentes estimulantes de la eritropoyesis (AEE) en pacientes con anemia asociada a enfermedad renal crónica (ERC), y valorar su relación con la respuesta frente a estos AEE. MATERIAL Y MÉTODOS: Estudio retrospectivo, observacional, de una cohorte de 198 pacientes con ERC que iniciaron tratamiento con epoetina-beta o darbepoetina-alfa, seguidos durante dos años. Se registraron variables basales, de efectividad (% de consecución de objetivos de hemoglobina (Hb), incremento porcentual de Hb) y adherencia (tasa de posesión de medicación). Se consideró no adherente al paciente cuya adherencia fue <90%. RESULTADOS: La adherencia global fue 89,6%, ligeramente superior en darbepoetina-alfa que en epoetina-beta; el 8,6% de los pacientes fueron no adherentes. El 87% cumplió el objetivo de Hb. Los valores de respuesta a AEE no variaron en función del grado de adherencia al tratamiento. CONCLUSIONES: La adherencia al tratamiento con AEE fue buena, sin diferencias según la respuesta
BACKGROUND: To establish adherence to treatment with erythropoiesis stimulating agents (ESA) in patients with anemia associated to chronic kidney disease (CKD), and analyze its relationship to response to ESA. METHODS: Retrospective study of a cohort of 198 patients with CKD who started treatment with epoetin-beta or darbepoetin-alpha, followed for two years. Basal characteristics, effectiveness (% of hemoglobin (Hb) target attainment, percentage increase of Hb) and adherence (medication possession rate) were registered. A non-adherent patient was one whose mean adherence was <90%. RESULTS: Average global adhesion was 89.6%, slightly higher in treatment with darbepoetin alpha than with epoetin beta; 8.6% of patients were non-adherents. Hb target was accomplished in 87% cases. Level of response to ESA treatment was independent of the degree of adherence to treatment. CONCLUSIONS: Adherence to ESA treatment was good, without differences related to degree of response
Subject(s)
Humans , Male , Female , Aged , Treatment Adherence and Compliance , Erythropoiesis/drug effects , Anemia/etiology , Renal Insufficiency, Chronic/complications , Cohort Studies , Epoetin Alfa/administration & dosage , Renal DialysisABSTRACT
A multicenter cohort study.The DialysisNet was previously developed for the management of hemodialysis (HD) patients based on the American Society for Testing and Materials Continuity of Care Records by metadata transformation. DialysisNet is a dialysis patient management program created by using the personal health record care platform to overcome the problems of registry studies, in real-time.Here, we aimed to investigate the pattern of treatment for renal anemia in HD patients using DialysisNet.We performed a multicenter cohort study among HD patients who were treated at one of the three Korean university-affiliated hospitals from January 2016 to December 2016. Subjects were divided into 4 hemoglobin variability groups by quartiles. The variable anemia treatment pattern was reviewed. To determine renal anemia treatment patterns, we automatically collected information on the practice of anemia treatment patterns such as erythropoietin stimulating agent (ESA) doses and administration frequencies, and targeted hemoglobin maintenance rate. Individual hemoglobin variabilities were expressed as (standard deviations)/(â(n/[n-1]).The records of 159 patients were analyzed (Hospital A: 35, Hospital B: 21, Hospital C: 103). Mean patients' age was 65.6â±â12.8 years, and 61.6% were men. Overall, hemoglobin level was 10.5[7.43;13.93]âg/dL. 158 (99.3%) patients were using ESA; and overall, the epoetin alfa dose was 33,000[4000;136,800]âU per week. Hemoglobin levels (Pâ=â.206) and epoetin alfa doses were similar (Pâ=â.924) for patients with different hemoglobin variabilities. The hemoglobin target maintenance rate was lower in the highest hemoglobin variability group than in the lowest variability group (Pâ=â.045).In this study, detailed information on the actual anemia treatment patterns were obtained using the DialysisNet. We expect that DialysisNet will simplify and improve the renal anemia management for both dialysis patients and health care providers.
Subject(s)
Anemia/etiology , Anemia/therapy , Databases, Factual , Epoetin Alfa/therapeutic use , Hematinics/therapeutic use , Renal Dialysis/adverse effects , Aged , Dose-Response Relationship, Drug , Electronic Health Records , Epoetin Alfa/administration & dosage , Female , Hematinics/administration & dosage , Hemoglobins , Humans , Male , Middle Aged , United StatesABSTRACT
The purpose of the work was to investigate mechanisms of erythropoietin-induced protection and accelerated recovery of kidneys and ureters from obstructive injury. Unilateral ureteral obstruction was established for 24, 48, and 72 h in C57BL/6 mice using a non-traumatic micro-clip followed by the microscopic quantification of ureteral peristalsis pre- and post-obstruction. Expression of erythropoietin, erythropoietin receptor, ß-common receptor, and downstream apoptosis-related markers was assessed by RT-PCR and immunohistochemistry in ureters and kidneys and compared to the respective organs on the contralateral side within each animal. Expression of genes in kidneys and ureters from mice treated with 20 IU of erythropoietin daily for 72 h prior to obstruction was compared to that of untreated mice following obstruction. Apoptosis in ureteral tissues after 72-h obstruction was assessed via TUNEL assay. Ureteral obstruction increased apoptosis in affected ureters, with peristaltic function halted following all periods of obstruction. Erythropoietin treatment suppressed apoptosis in obstructed tissues and increased the percentage of mice retaining ureteral function immediately following obstruction reversal. Erythropoietin, erythropoietin receptor, Bcl-2, and Bcl-xl mRNA expression were down-regulated, while phospho-Nf-ĸb p65 was up-regulated in ureteral epithelia following obstruction. Erythropoietin treatment induced anti-apoptotic signaling via down-regulated Bax mRNA expression and abrogated phospho-Nf-ĸb p65. Erythropoietin-induced protection of ureteral function and accelerated recovery post-obstruction removal is mediated via anti-apoptotic mechanisms. Ureteral function is disrupted even following obstruction removal, negatively affecting renal function due to delayed recovery. Thus, our results represent a potential target for the development of safe therapeutic agents aimed at improving functional recovery from obstructive injury.
Subject(s)
Epoetin Alfa , Kidney , Protective Agents , Ureter , Ureteral Obstruction/drug therapy , Animals , Apoptosis/drug effects , Epoetin Alfa/administration & dosage , Epoetin Alfa/pharmacology , Female , Kidney/drug effects , Kidney/injuries , Mice , Mice, Inbred C57BL , Protective Agents/administration & dosage , Protective Agents/pharmacology , Recovery of Function , Ureter/drug effects , Ureter/injuriesABSTRACT
PURPOSE: Pre-operative anaemia treatment has been associated with reduced morbidity in joint arthroplasty. This study examined the impact of a surgical prescription of epoetin (EPO) in contemporary total hip arthroplasty (THA). METHODS: We conducted a comparative study in a series of 1402 primary THAs performed in patients all having a pre-operative haemoglobin (Hb) level documented four to eight weeks before THA surgery. In group A (647 hips), one subcutaneous injection of 40,000 IU EPO once a week for four weeks was prescribed at the discretion of anaesthetist during the pre-operative visit in patients with pre-operative Hb between 10 and 13 g/dl. In group S comprising the remaining 755 hips, an amended EPO therapy including two injections of 20,000 to 40,000 IU was prescribed by the surgeon in patients with Hb less than 12 g/dl deemed at high risks to be transfused following THA. Primary study endpoint was the bleeding index (BI). RESULTS: EPO therapy was delivered in 43 patients (6.7%) in group A and in 26 patients (3.4%) in group S (p = 0.006). The mean total dose of EPO administrated was 115,349 IU in group A versus 75,200 IU in group S (p < 0.001). The mean BI were 2.7 ± 1.0 in group A and 2.8 ± 1.0 g/dl in group S (p = 0.375). No patient was blood-transfused up to post-operative day seven in group S versus five patients in group A (p = 0.021). CONCLUSIONS: The amended protocol does not lead to increased peri-operative bleeding. Advances in intra-operative methods to reduce the bleeding allow changing indications of EPO in patients undergoing THA with a low level of Hb.
Subject(s)
Anemia/drug therapy , Arthroplasty, Replacement, Hip , Epoetin Alfa/administration & dosage , Hematinics/administration & dosage , Joint Diseases/surgery , Middle Aged , Administration, Oral , Aged , Aged, 80 and over , Anemia/complications , Anemia/therapy , Arthroplasty, Replacement, Hip/adverse effects , Blood Transfusion , Female , Humans , Injections, Subcutaneous , Iron Compounds/administration & dosage , Joint Diseases/complications , Male , Prospective StudiesABSTRACT
OBJECTIVES: Intravenous iron and erythropoiesis-stimulating agents are used to manage anemia in chronic hemodialysis patients. The interchangeability between intravenous iron sucrose preparations is still debated. We evaluated how cost and effectiveness were impacted when chronic hemodialysis patients were switched from an original iron sucrose product to an iron sucrose similar preparation. METHODS: A single center sequential observational retrospective study was conducted at a French hospital. The same patients were followed during two 24-week periods (iron sucrose in period P1; and iron sucrose similar in period P2). Anemia-related treatment costs were assessed in P1 and P2 from a hospital perspective. Sensitivity analyses were performed to assess the robustness of the results. RESULTS: Our study included 109 patients (105 analyzed patients and 4 patients with missing data). The mean hemoglobin level was not different between P1 and P2 (p = 0.92). The mean differential cost per patient was + 13.90 (P2 - P1). The factors with the biggest impact on this result were the prices of epoetin alfa and iron sucrose. CONCLUSION: This cost minimization analysis suggests that for chronic hemodialysis patients, iron sucrose and iron sucrose similar have the same efficacy and that using iron sucrose similar was more expensive in 66.7% of iterations.
Subject(s)
Anemia/drug therapy , Ferric Oxide, Saccharated/administration & dosage , Hematinics/administration & dosage , Renal Dialysis , Administration, Intravenous , Aged , Anemia/economics , Costs and Cost Analysis , Drug Costs , Epoetin Alfa/administration & dosage , Epoetin Alfa/economics , Female , Ferric Oxide, Saccharated/economics , France , Hematinics/economics , Humans , Male , Middle Aged , Retrospective StudiesABSTRACT
BACKGROUND: treatment of erythropoietin (EPO) is essential in chronic kidney disease (CKD) patients to maintain optimal hemoglobin (Hb) level. Renogen is a biosimilar epoetin-α, and Eprex is the originator epoetin-α. This study aimed to compare the efficacy and tolerance of Renogen with Eprex in CKD anemia. METHODS: Renogen and Eprex were compared in a randomized (2:1), open-label study for 8 weeks, proceeded by 4 weeks adjustment (maintenance) phase, in anemic CKD patients undergoing HD in Cipto Mangunkusumo General Hospital, Jakarta, from June 2017 to October 2018. RESULTS: a total of 45 patients (31 received biosimilar EPO and 14 received originator EPO) were included in the study. At baseline, mean (SD) Hb levels were 10.9 (0.74) g/dL and 10.9 (0.61) g/dL in biosimilar and originator EPO groups, respectively. At end of study (8 weeks), mean (SD) Hb levels were 10.5 (1.28) g/dL and 11.0 (1.13) g/dL in biosimilar EPO and originator EPO groups, respectively. The proportion of patients with Hb levels maintained within the target range (>10 g/dL) during 8 weeks randomization phase were 58.1% and 71.4% in biosimilar EPO and originator EPO, respectively (p=0.60; NS). There were no significant difference in epoetin dose between the 2 groups, and there was no drug-related adverse event in either group. CONCLUSION: Hb level at >10 g/dL could be maintained for 8 weeks of treatment with both originator and biosimilar EPO (more consistent with originator EPO and more fluctuations with biosimilar EPO), with similar epoetin dose and no drug-related adverse event.
Subject(s)
Anemia/drug therapy , Biosimilar Pharmaceuticals/administration & dosage , Epoetin Alfa/administration & dosage , Hematinics/administration & dosage , Renal Insufficiency, Chronic/complications , Adult , Anemia/etiology , Female , Hemoglobins/analysis , Humans , Indonesia , Injections, Intravenous , Male , Middle Aged , Treatment OutcomeABSTRACT
Anemia management with erythropoiesis stimulating agents is a challenging task in hemodialysis patients since their response to treatment varies highly. In general, it is difficult to achieve and maintain the predefined hemoglobin (Hgb) target levels in clinical practice. The aim of this study is to develop a fully personalizable controller scheme to stabilize Hgb levels within a narrow target window while keeping drug doses low to mitigate side effects. First in-silico results of this framework are presented in this paper. Based on a model of erythropoiesis we formulate a non-linear model predictive control (NMPC) algorithm for the individualized optimization of epoetin alfa (EPO) doses. Previous to this work, model parameters were estimated for individual patients using clinical data. The optimal control problem is formulated for a continuous drug administration. This is currently a hypothetical form of drug administration for EPO as it would require a programmable EPO pump similar to insulin pumps used to treat patients with diabetes mellitus. In each step of the NMPC method the open-loop problem is solved with a projected quasi-Newton method. The controller is successfully tested in-silico on several patient parameter sets. An appropriate control is feasible in the tested patients under the assumption that the controlled quantity is measured regularly and that continuous EPO administration is adjusted on a daily, weekly or monthly basis. Further, the controller satisfactorily handles the following challenging problems in simulations: bleedings, missed administrations and dosing errors.
Subject(s)
Anemia/drug therapy , Drug Therapy, Computer-Assisted/methods , Epoetin Alfa/administration & dosage , Hematinics/administration & dosage , Renal Dialysis/adverse effects , Anemia/blood , Anemia/diagnosis , Anemia/etiology , Dose-Response Relationship, Drug , Drug Administration Schedule , Drug Therapy, Computer-Assisted/instrumentation , Epoetin Alfa/pharmacokinetics , Erythropoiesis/drug effects , Erythropoiesis/physiology , Hematinics/pharmacokinetics , Hemoglobins/analysis , Humans , Infusion Pumps , Models, Biological , Nonlinear DynamicsABSTRACT
Hypertension among patients on hemodialysis is predominantly systolic (either isolated or combined with diastolic hypertension), whereas the scenario of isolated diastolic hypertension is rare and more common in younger patients. Uncontrolled hypertension that persists despite aggressive antihypertensive drug therapy is a reflection of the volume overload that is a prominent mediator of systolic and diastolic BP elevation. Clinical-trial evidence supports the notion that dry-weight probing is an effective strategy to improve BP control, even when overt clinical signs and symptoms of volume overload are not present. Accelerated arterial stiffness influences the patterns and rhythms of interdialytic ambulatory BP and is a major determinant of isolated systolic hypertension in hemodialysis. Posthoc analyses of the Hypertension in Hemodialysis patients treated with Atenolol or Lisinopril (HDPAL) trial, however, suggest that arterial stiffness does not make hypertension more resistant to therapy and is unable to predict the treatment-induced improvement in left ventricular hypertrophy. A combined strategy of sodium restriction, dry-weight adjustment, and antihypertensive medication use was effective in improving ambulatory BP control regardless of the severity of underlying arteriosclerosis in HDPAL. Other nonvolume-dependent mechanisms, such as erythropoietin use, appear to be also important contributors and should be taken into consideration, particularly in younger hemodialysis patients with diastolic hypertension. In this article, we explore the role of volume overload, arterial stiffness, and erythropoietin use as causes of systolic vs diastolic hypertension in patients on hemodialysis. We conclude with clinical practice recommendations and with a call for a "volume-first" approach when managing hemodialysis hypertension.
Subject(s)
Epoetin Alfa/administration & dosage , Hypertension/drug therapy , Kidney Failure, Chronic/therapy , Renal Dialysis/adverse effects , Water-Electrolyte Imbalance/etiology , Atenolol/administration & dosage , Diastole/physiology , Erythropoietin/administration & dosage , Erythropoietin/adverse effects , Female , Follow-Up Studies , Humans , Hypertension/epidemiology , Hypertension/etiology , Incidence , Kidney Failure, Chronic/diagnosis , Lisinopril/administration & dosage , Male , Renal Dialysis/methods , Risk Assessment , Systole/physiology , Vascular Stiffness/drug effects , Water-Electrolyte Imbalance/physiopathology , Water-Electrolyte Imbalance/therapyABSTRACT
Erythropoietin (EPO) has been linked to cardioprotective effects. However, its effects during the aging process are little known. We investigated the effect of EPO administration on hemodynamic parameters, cardiac function, oxidative damage, and erythropoietin receptor (EPOR) expression pattern in the hypovolemic state. EPO was administered (1000 IU/kg/3 days) and then acute hemorrhage (20% blood loss) was induced in young and adult rats. There was no difference in plasmatic EPO in either age group. The hemodynamic basal condition was similar, without alterations in renal function and hematocrit, in both age groups. After bleeding, both EPO-treated age groups had increased blood pressure at the end of the experimental protocol, being greater in adult animals. EPO attenuated the tachycardic effect. Ejection fraction and fractional shortening were higher in adult EPO-treated rats subjected to hemorrhage. In the left ventricle, young and adult EPO-treated rats subjected to bleeding showed an increased EPOR expression. A different EPOR expression pattern was observed in the adult right atrial tissue, compared with young animals. EPO treatment decreased oxidative damage to lipids in both age groups. EPO treatment before acute hemorrhage improves cardiovascular function during the aging process, which is mediated by different EPOR pattern expression in the heart tissue.
Subject(s)
Cardiovascular System/drug effects , Epoetin Alfa/administration & dosage , Hematinics/administration & dosage , Hemodynamics/drug effects , Hemorrhage/drug therapy , Ventricular Function, Left/drug effects , Age Factors , Animals , Cardiovascular System/metabolism , Cardiovascular System/physiopathology , Disease Models, Animal , Hemorrhage/metabolism , Hemorrhage/physiopathology , Lipid Peroxidation/drug effects , Male , Myocardium/metabolism , Oxidative Stress/drug effects , Rats, Sprague-Dawley , Receptors, Erythropoietin/agonists , Receptors, Erythropoietin/metabolismABSTRACT
IL-17-producing CD4+ cells (TH17) are pathogenically linked to autoimmunity including to autoimmune kidney disease. Erythropoietin's (EPO) newly recognized immunoregulatory functions and its predominant intra-renal source suggested that EPO physiologically regulates TH17 differentiation, thereby serving as a barrier to the development of autoimmune kidney disease. Using in vitro studies of human and murine cells and in vivo models, we show that EPO ligation of its receptor (EPO-R) on CD4+ T cells directly inhibits TH17 generation and promotes trans-differentiation of TH17 into IL-17-FOXP3+CD4+ T cells. Mechanistically, EPO/EPO-R ligation abrogates upregulation of SGK1 gene expression and blocks p38 activity to prevent SGK1 phosphorylation, thereby inhibiting RORC-mediated transcription of IL-17 and IL-23 receptor genes. In a murine model of TH17-dependent aristolochic acid (ArA)-induced, interstitial kidney disease associated with reduced renal EPO production, we demonstrate that transgenic EPO overexpression or recombinant EPO (rEPO) administration limits TH17 formation and clinical/histological disease expression. EPO/EPO-R ligations on CD4+ T cells abrogate, while absence of T cell-expressed EPO-R augments, TH17 induction and clinical/histological expression of pristane-induced glomerulonephritis (associated with decreased intrarenal EPO). rEPO prevents spontaneous glomerulonephritis and TH17 generation in MRL-lpr mice. Together, our findings indicate that EPO physiologically and therapeutically modulate TH17 cells to limit expression of TH17-associated autoimmune kidney disease.
Subject(s)
Erythropoietin/metabolism , Immediate-Early Proteins/metabolism , Lupus Nephritis/immunology , Nephritis, Interstitial/immunology , Protein Serine-Threonine Kinases/metabolism , Th17 Cells/immunology , Animals , Aristolochic Acids/toxicity , Cells, Cultured , Disease Models, Animal , Epoetin Alfa/administration & dosage , Erythropoietin/genetics , Female , Humans , Interleukin-17/immunology , Interleukin-17/metabolism , Lupus Nephritis/diagnosis , Lupus Nephritis/drug therapy , Male , Mice , Mice, Inbred MRL lpr , Mice, Transgenic , Nephritis, Interstitial/chemically induced , Phosphorylation/immunology , Primary Cell Culture , Receptors, Erythropoietin/metabolism , Receptors, Interleukin/metabolism , Severity of Illness Index , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism , Th17 Cells/metabolismABSTRACT
Objectives: There is a lack of data in Panama on the potential differences in total healthcare professional (HCP) time between routine administrations of short-acting erythropoietin simulating agents (ESAs) (i.e. epoetin alfa) and continuous erythropoietin receptor activator (CERA) (i.e. methoxy polyethylene glycol-epoetin beta). This study aimed to quantify the HCP time associated with a single administration of epoetin alfa and CERA for the treatment of anemic patients with chronic kidney disease (CKD) on hemodialysis. Methods: This was a multi-center, cross-sectional study, using a time-and-motion methodology. Costs related to HCP time and consumables usage associated with administration of epoetin alfa and CERA were estimated. Results: Based on 60 administrations of either CERA or epoetin alfa, the estimated savings in mean total active HCP time were 2.34 (95% confidence interval = 1.87-2.81) min (-30%) per administration. When extrapolating to a full year's treatment with intravenous ESA, it would require a total of 20.3 (95% CI = 19.90-20.71) h of HCP time for epoetin alfa vs 1.1 (95% CI = 1.01-1.19) h for CERA per patient per year. Estimated savings in active HCP time per patient per year were 19.20 (95% CI = 19.20-19.21) h (-95%). This, in turn, translates into staff cost efficiency that favors Mircera with an estimated annual saving of $78.24 (95% CI = 78.24-78.28) (-95%) per patient. Conclusions: Data from a real-world setting showed that the adoption of CERA could potentially lead to a reduction in active HCP time. Highlights Few comparative data have explored the costs and potential savings of using long-acting erythropoietin-stimulating agents (ESA) instead of short-acting ESAs to treat anemia in CKD patients on hemodialysis. This time-and-motion study shows that use of CERA reduces total healthcare professional time and could represent a save for an institution in a real-world setting in Panama.
Subject(s)
Epoetin Alfa/economics , Erythropoietin/economics , Health Personnel/economics , Hematinics/economics , Polyethylene Glycols/economics , Anemia/drug therapy , Anemia/etiology , Cross-Sectional Studies , Drug Costs , Epoetin Alfa/administration & dosage , Erythropoietin/administration & dosage , Female , Health Personnel/statistics & numerical data , Hematinics/administration & dosage , Humans , Male , Panama , Polyethylene Glycols/administration & dosage , Renal Dialysis/adverse effects , Renal Insufficiency, Chronic/therapy , Time FactorsABSTRACT
BACKGROUND: Molidustat, a novel hypoxia-inducible factor-prolyl hydroxylase inhibitor, is being investigated for the treatment of anemia associated with chronic kidney disease (CKD). The efficacy and safety of molidustat were recently evaluated in three 16-week phase 2b studies. Here, we report the results of two long-term extension studies of molidustat. METHODS: Both studies were parallel-group, open-label, multicenter studies of ≤36 months' duration, in patients with anemia due to CKD, and included an erythropoiesis-stimulating agent as active control. One study enrolled patients not receiving dialysis (n = 164), and the other enrolled patients receiving hemodialysis (n = 88). The primary efficacy variable for both studies was change in blood hemoglobin (Hb) level from baseline to each post-baseline visit, and safety outcomes included adverse events (AEs). RESULTS: In patients not on dialysis, the mean ± SD Hb concentrations at baseline were 11.28 ± 0.55 g/dL for molidustat and 11.08 ± 0.51 g/dL for darbepoetin. The mean ± SD blood Hb concentrations throughout the study (defined as mean of each patient's overall study Hb levels) were 11.10 ± 0.508 and 10.98 ± 0.571 g/dL in patients treated with molidustat and darbepoetin, respectively. Similar proportions of patients reported at least one AE in the molidustat (85.6%) and darbepoetin (85.7%) groups. In patients on dialysis, mean ± SD Hb levels at baseline were 10.40 ± 0.70 and 10.52 ± 0.53 g/dL in the molidustat and epoetin groups, respectively. The mean ± SD blood Hb concentrations during the study were 10.37 ± 0.56 g/dL in the molidustat group and 10.52 ± 0.47 g/dL in the epoetin group. Proportions of patients who reported at least one AE were 91.2% in the molidustat group and 93.3% in the epoetin group. CONCLUSIONS: Molidustat was well tolerated for up to 36 months and appears to be an effective alternative to darbepoetin and epoetin in the long-term management of anemia associated with CKD.