Pharmacokinetic and pharmacodynamic study of three products of epoetin alfa as single subcutaneous dose in healthy volunteers.

Hemax® is an epoetin alfa product developed by Biosidus S.A. in Argentina at the end of the 1980s and has been present in that market since 1991. The initial presentation was a lyophilized powder containing albumin as stabilizer, to best adapt to environmental conditions in developing countries; more recently, a prefilled syringe, albumin-free presentation was developed, since this presentation has become the preferred standard in many markets. The primary objective was to compare the pharmacokinetic profile of different formulations of epoetin alfa after a single subcutaneous administration to healthy volunteers of 40 000 IU of Eprex/Erypo® and Hemax® PFS. This clinical trial was conceived following an open-label, randomized, three-way three-period cross-over balanced, and sequential design. The study was conducted on 24 healthy volunteers. To analyze similarity between Hemax® PFS and the innovator product, Eprex®, area under the curve (AUC) and Cmax of both products have been compared. The 90% CI lower limit for the geometric mean ratios was higher than 80% for any comparisons, and the 90% CI upper limit for these geometric ratios was below 125% for all the comparisons made, thus demonstrating equivalence between both products. The comparison between Hemax® PFS and Eprex® resulted in similar 90% CI for Cmax , AUC(0-120 h) and AUC(0-inf) ratios, all of them within the 80-125% interval, with a power above 95% for each ratio. These findings suggest biosimilar patterns for absorption velocity (with Tmax close to 15 h), absorption extent, and elimination (with an elimination half-life close to 25-30 h for each formulation).

Applying metabolomics to detect growth hormone administration in athletes: Proof of concept.

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.

Optimal EPO dosing in hemodialysis patients using a non-linear model predictive control approach.

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.

Structure-Function Relationships for Recombinant Erythropoietins: A Case Study From a Proposed Manufacturing Change With Implications for Erythropoietin Biosimilar Study Designs.

Comparability studies used to assess a proposed manufacturing change for a biological product include sensitive analytical studies to confirm there are no significant differences in structural or functional attributes that may contribute to clinically meaningful changes in efficacy or safety. When a proposed change is relatively complex or when clinically relevant differences between the product before and after the change cannot be ruled out based on analytical studies, nonclinical and clinical bridging studies are generally required to confirm overall comparability. In this study, we report findings from a comparability assessment of epoetin alfa before and after a proposed manufacturing process change. Although differences in glycosylation attributes were observed, these were initially believed to be irrelevant to the product's pharmacology. This assumption was initially supported via nonclinical and clinical pharmacology studies, but a clinically meaningful difference in potency was ultimately observed in a phase 3 clinical study conducted in a sensitive patient population using a sensitive study design. These results indicate that the nonclinical assessments of structure-function relationships were insufficiently sensitive to identify clinically relevant differences resulting from differences in the glycosylation profile. This case study highlights important findings that may be relevant in the development of biosimilar epoetin alfa products.

HX575: established biosimilarity in the treatment of renal anemia and 10 years of clinical experience.

Erythropoiesis-stimulating agents, such as recombinant human erythropoietin, are commonly used for the treatment of anemia in patients with chronic kidney disease (CKD). In 2007, HX575 (Binocrit®) became the first biosimilar epoetin alfa to be approved by the European Medicines Agency (EMA). The decision to approve a biosimilar is based on the totality of evidence obtained in a comprehensive comparability exercise that involves extensive analytical characterization, nonclinical studies and clinical studies. The development process for HX575 included extensive analytical characterization and comparison with the reference epoetin alfa. This was followed by a clinical development program, comprising Phase I pharmacokinetic/pharmacodynamic studies to show bioequivalence to the reference medicine and a confirmatory Phase III study to demonstrate therapeutic effectiveness in anemia related to CKD. In addition to the comparability exercises, extensive clinical experience over the last decade also confirms that HX575 provides an effective treatment for CKD-related anemia, with a favorable safety profile. Growing clinical experience with EMA-approved biosimilars, including HX575, should offer additional reassurance to health care professionals and patients that these agents are as effective and well tolerated as others in the therapeutic class.

Erythropoietin Does Not Alter Serum Profiles of Neuronal and Axonal Biomarkers After Traumatic Brain Injury: Findings From the Australian EPO-TBI Clinical Trial.

OBJECTIVE: To determine profiles of serum ubiquitin carboxy-terminal hydrolase L1 and phosphorylated neurofilament heavy-chain, examine whether erythropoietin administration reduce their concentrations, and whether biomarkers discriminate between erythropoietin and placebo treatment groups. DESIGN: Single-center, prospective observational study. SETTING: A sub-study of the erythropoietin-traumatic brain injury clinical trial, conducted at the Alfred Hospital, Melbourne, Australia. PATIENTS: Forty-four patients with moderate-to-severe traumatic brain injury. INTERVENTIONS: Epoetin alfa 40,000 IU or 1 mL sodium chloride 0.9 as subcutaneous injection within 24 hours of traumatic brain injury. MEASUREMENTS AND MAIN RESULTS: Ubiquitin carboxy-terminal hydrolase L1, phosphorylated neurofilament heavy-chain, and erythropoietin concentrations were measured in serum by enzyme-linked immunosorbent assay from D0 (within 24 hr of injury, prior to erythropoietin/vehicle administration) to D5. Biomarker concentrations were compared between injury severities, diffuse versus focal traumatic brain injury and erythropoietin or placebo treatment groups. Ubiquitin carboxy-terminal hydrolase L1 peaked at 146.0 ng/mL on D0, significantly decreased to 84.30 ng/mL on D1, and declined thereafter. Phosphorylated neurofilament heavy-chain levels were lowest at D0 and peaked on D5 at 157.9 ng/mL. D0 ubiquitin carboxy-terminal hydrolase L1 concentrations were higher in diffuse traumatic brain injury. Peak phosphorylated neurofilament heavy-chain levels on D3 and D4 correlated with Glasgow Outcome Score-Extended, predicting poor outcome. Erythropoietin did not reduce concentrations of ubiquitin carboxy-terminal hydrolase L1 or phosphorylated neurofilament heavy-chain. CONCLUSIONS: Serum ubiquitin carboxy-terminal hydrolase L1 and phosphorylated neurofilament heavy-chain increase after traumatic brain injury reflecting early neuronal and progressive axonal injury. Consistent with lack of improved outcome in traumatic brain injury patients treated with erythropoietin, biomarker concentrations and profiles were not affected by erythropoietin. Pharmacokinetics of erythropoietin suggest that the dose given was possibly too low to exert neuroprotection.

Comparable pharmacokinetics and pharmacodynamics of two epoetin alfa formulations Eporon® and Eprex® following a single subcutaneous administration in healthy male volunteers.

PURPOSE: This study aimed to assess and compare the pharmacokinetic (PK) and pharmacodynamic (PD) properties following a single subcutaneous injection of epoetin alfa (Eporon®) with those of the comparator (Eprex®) in healthy male subjects. SUBJECTS AND METHODS: A randomized, double-blind, two-sequence, crossover study was conducted. Subjects were randomly assigned to receive a single dose, that is, 4,000 IU, of the test or comparator epoetin alfa. After 4 weeks, all subjects received the alternative formulation. The primary PK parameters, maximum observed concentration (Cmax) and area under the curve extrapolated to infinity (AUCinf), were calculated with the serum erythropoietin (EPO) concentrations from blood samples collected for 144 h after dosing. The reticulocyte, hematocrit, hemoglobin and red blood cell counts were measured up to 312 h as PD markers. The primary PD parameters, maximum observed effect (Emax) and area under the effect curve (AUEC), were obtained from the baseline-corrected reticulocyte count. The serum EPO concentration and the reticulocyte count were used to assess the concentration-response relationship. The tolerability and immunogenicity profiles were assessed together. RESULTS: Forty-two subjects completed the study. The mean EPO concentration-time profiles were comparable between the two formulations. The geometric mean ratios (90% CI) of the Cmax and AUCinf were 0.908 (0.843-0.978) and 1.049 (0.999-1.101), respectively, both of which were within the regulatory range of 0.80-1.25. Additionally, the PD and tolerability profiles were similar between the two formulations. The time-matched serum EPO concentration and PD markers presented a counterclockwise hysteresis, suggesting a time delay between the measured concentration and the response. Both formulations were well tolerated, and production of anti-drug antibodies was not observed. CONCLUSION: The two epoetin alfa formulations had similar PK, PD and tolerability profiles. Furthermore, both formulations had a similar time-matched serum EPO concentration and erythropoietic response profile. Thus, the two formulations are expected to be used interchangeably in clinical settings.

Pharmacokinetic and Pharmacodynamic Equivalence of Epoetin Hospira and Epogen After Single Subcutaneous Doses to Healthy Male Subjects.

PURPOSE: The purpose of this study was to evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) equivalence of single 100 U/kg subcutaneous doses of Epoetin Hospira and Epogen in healthy male subjects as part of an overall program to demonstrate biosimilarity of Epoetin Hospira to the reference product Epogen. METHODS: This single-center, open-label, randomized, 2-period, crossover study was conducted in 81 healthy male subjects. Subjects were randomized to Sequence 1, in which they received 100 U/kg of Epoetin Hospira or to sequence 2, in which they received 100 U/kg Epogen subcutaneously in the first study period and the alternative treatment in the second study period. Blood was collected for determination of baseline-adjusted epoetin concentrations (BAECs) for pharmacokinetics and for determination of reticulocyte percentage of total erythrocytes for pharmacodynamics throughout both study periods. The primary PK end points were the geometric mean ratios (GMRs) of the 2 treatments for AUC0-t and Cmax based on the BAEC, and the primary PD end points were the GMRs of the 2 treatments for AUC0-t and Cmax for reticulocyte percentage. FINDINGS: The GMRs of Epoetin Hospira to Epogen for the BAEC-derived PK parameters were 1.05 for AUC0-t with a 90% CI of 1.01 to 1.11, and 1.09 for Cmax with a 90% CI of 1.01 to 1.18, with both 90% CIs contained within the prespecified equivalence margin of 0.80 to 1.25. The GMRs (Epoetin Hospira/Epogen) for the reticulocyte percentage-derived PD parameters were 1.01 for AUC0-t with a 95% CI of 0.98 to 1.05, and 1.02 for Cmax with a 95% CI of 0.98 to 1.06, with both 95% CIs contained within the prespecified equivalence margin of 0.80 to 1.25. Overall, the adverse events were of similar frequency (11.7% and 13.9% for Epoetin Hospira and Epogen, respectively) and severity between treatments. One subject had a positive anti- recombinant human erythropoietin antibody result by radioimmunoprecipitation assay before dosing and throughout the conduct of the study with negative neutralizing antibodies and with no evidence of clinical deterioration or impact on the pharmacokinetics, pharmacodynamics, or safety. IMPLICATIONS: The results of this study established the PK and PD equivalence of single 100 U/kg subcutaneous doses of the proposed biosimilar Epoetin Hospira to the reference product Epogen in healthy male subjects and support the overall demonstration of biosimilarity of Epoetin Hospira and Epogen.

Pharmacodynamic and Pharmacokinetic Equivalences of Epoetin Hospira and Epogen(®) After Multiple Subcutaneous Doses to Healthy Male Subjects.

PURPOSE: The purpose of this study was to evaluate the pharmacodynamic (PD) and pharmacokinetic (PK) equivalences of multiple doses of the proposed biosimilar Epoetin Hospira to the reference product Epogen(⁎), when each is administered three times per week over 28 days to healthy male subjects METHODS: This single center, open-label, randomized, parallel group study was conducted in 129 healthy male subjects. Subjects were randomized to receive 100 U/kg Epoetin Hospira or 100 U/kg Epogen, each administered subcutaneously 3 times per week over 28 days. Blood was collected for determination of hemoglobin (Hb) concentrations for PD properties and for determination of epoetin concentrations for PK properties. The primary PD end point was the geometric mean ratio (GMR) of the 2 treatments for area under the effect curve for Hb from day 1 through 48 hours after the final dose of study drug administration on day 26, and the primary PK end point was the GMR of the 2 treatments for AUC0-48 and Cmax for epoetin after the final dose of study drug on day 26. FINDINGS: The GMR (Epoetin Hospira/Epogen) for the area under the effect curve for Hb from day 1 through 48 hours after the final dose of study drug administration on day 26 was 1.006 with a 95% CI of 0.996 to 1.016, which was contained within the prespecified equivalence margin of 0.965 to 1.035. The GMRs (Epoetin Hospira/Epogen) for the epoetin-derived PK parameters were 0.974 for AUC0-48 with a 90% CI of 0.896 to 1.059, and 0.938 for Cmax with a 90% CI of 0.839 to 1.049, with both 90% CIs contained within the prespecified equivalence margin of 0.80 to 1.25. The incidence (21.2% and 23.8% for Epoetin Hospira and Epogen, respectively) and severity of adverse events were similar between the 2 groups. One subject in each treatment group had a positive recombinant human erythropoietin antibody result by radioimmunoprecipitation assay before dosing and throughout study conduct with negative immunoglobulin M and neutralizing antibodies and with no evidence of clinical deterioration or of impact on PD, PK, or safety profile. IMPLICATIONS: The results of this study established PD and PK equivalences of multiple subcutaneous doses of the proposed biosimilar Epoetin Hospira to the reference product Epogen in healthy male subjects, and supported the overall demonstration of biosimilarity of Epoetin Hospira and Epogen.

Pharmacokinetic and Pharmacodynamic Comparison of Two Recombinant Human Erythropoietin Formulations, PDA10 and Eprex, in Healthy Korean Male Volunteers: A Randomized, Double-Blinded, Single-Dose, Two-Period Crossover Study.

BACKGROUND AND OBJECTIVES: A new biosimilar human recombinant epoetin alfa product (PDA10) has been developed by PanGen Biotech Inc., Korea. This study was planned to demonstrate the pharmacokinetic and pharmacodynamic comparability of PDA10 to an existing epoetin alfa (Eprex) after a single intravenous administration to healthy adult male volunteers. METHODS: A randomized, double-blinded, single-dose, crossover study was conducted in 30 subjects. The subjects were assigned randomly to one of two sequence groups, and single doses of 100 IU/kg PDA10 or Eprex were administered intravenously on each of 2 treatment days separated by a 4-week washout period. Plasma erythropoietin concentrations were measured using an enzyme-linked immunosorbent assay and the pharmacokinetic parameters of the two treatments were compared. The time course and area under the effect curve (AUEC) of absolute reticulocyte counts were used as surrogate parameters for the pharmacodynamic evaluation. Adverse events (AEs) were recorded. RESULTS: A total of 30 subjects were enrolled, and 27 completed the study. The geometric mean ratios (PDA10/Eprex) of erythropoietin for maximum plasma concentration (C max) and area under the plasma concentration-time curve to the last measurable concentration (AUC0-last) after intravenous administration of 100 IU/kg were 1.00 (90% confidence interval [CI] 0.96-1.05) and 0.96 (90% CI 0.93-1.00). The absolute reticulocyte counts of PDA10 and Eprex were similar, as determined from the maximum reticulocyte count and AUEC0-last values. Treatment-emergent AEs were mild and occurred in seven subjects. CONCLUSION: PDA10 and Eprex met the regulatory criteria for bioequivalence with respect to their pharmacokinetic profiles and pharmacodynamic actions.

Assessment of hemoglobin responsiveness to epoetin alfa in patients on hemodialysis using a population pharmacokinetic pharmacodynamic model.

A population pharmacokinetic pharmacodynamic (PK/PD) model describing the effect of epoetin alfa on hemoglobin (Hb) response in hemodialysis patients was developed. Epoetin alfa pharmacokinetics was described using a linear 2-compartment model. PK parameter estimates were similar to previously reported values. A maturation-structured cytokinetic model consisting of 5 compartments linked in a catenary fashion by first-order cell transfer rates following a zero-order input process described the Hb time course. The PD model described 2 subpopulations, one whose Hb response reflected epoetin alfa dosing and a second whose response was unrelated to epoetin alfa dosing. Parameter estimates from the PK/PD model were physiologically reasonable and consistent with published reports. Numerical and visual predictive checks using data from 2 studies were performed. The PK and PD of epoetin alfa were well described by the model.

Estudio de la efectividad de tres esquemas de administración de factores estimuladores de la eritropoyesis en pacientes con anemia asociada a quimioterapia por una neoplasia sólida o hematológica / Study of effectiveness of 3 schedules of administration of erythropoietic colonystimulating factors in anemic patients under chemotherapy for solid or hematology malignancy

FUNDAMENTO Y OBJETIVO: El tratamiento de la anemia asociada a quimioterapia en los pacientes con cáncerha variado de forma notable en los últimos años. El objetivo de este estudio ha sido verificar si losesquemas terapéuticos de administración de eritropoyetina más utilizados en la práctica clínica habitualpresentan una efectividad equivalente.PACIENTES Y MÉTODO: Se han revisado los tratamientos correspondientes a 1.103 pacientes con tumoressólidos o neoplasias hematológicas que incluyeron factores estimuladores de la eritropoyesis desdeenero de 2003 a abril de 2006. Después de aplicar un algoritmo de selección se obtuvieron 170 casos:55 tratados con epoetina alfa, a dosis de 10.000 U 3 veces por semana; 63 con darbepoetinaalfa, 150 μg por semana, y 52 con darbepoetina alfa, 500 μg cada 3 semanas. Las variables principalesutilizadas para comparar la efectividad fueron el incremento de la hemoglobina plasmática duranteel tratamiento y el porcentaje de pacientes que consiguieron valores de hemoglobina iguales o superioresa 120 g/l.RESULTADOS: Las diferencias entre la cifra máxima de hemoglobina alcanzada en el período de tratamientoy la inicial, así como las diferencias entre las cifras de hemoglobina final y la inicial, fueron similaresen los 3 grupos. El porcentaje de pacientes que alcanzaron durante el tratamiento y al final deéste un valor de hemoglobina superior o igual a 120 g/l fue equivalente para los grupos de 10.000 Ude epoetina alfa 3 veces por semana y 150 μg de darbepoetina alfa por semana. Dicho porcentaje fueinferior en los pacientes del grupo que recibió 500 μg de darbepoetina alfa cada 3 semanas.CONCLUSIONES: En los pacientes con anemia asociada a quimioterapia por una neoplasia sólida o hematológica,los tratamientos con epoetina alfa a dosis de 10.000 U 3 veces por semana y darbepoetinaalfa, 150 μg por semana, han mostrado ser igualmente eficaces en todos los parámetros estudiados,mientras que la darbepoetina alfa a dosis de 500 μg cada 3 semanas no lo fue en uno de ellos

BACKGROUND AND OBJECTIVE: The treatment of chemotherapy associated anemia in patients with cancerhas varied greatly in recent years. The objective of this study was to verify whether the most frequentlyused therapeutic schedules of erythropoietin administration demonstrate equivalent effectiveness.PATIENTS AND METHOD: Treatments corresponding to 1,103 patients with cancer receiving treatment witherythropoietic colony-stimulating factors from January 2003 to April 2006 were reviewed. After applyinga selection algorithm, 170 cases were analysed: 55 treated with epoetin alpha 10,000 IU 3 timesper week, 63 receiving darbepoetin alpha 150 μg weekly and 52 treated with darbepoetin alpha500 μg every 3 weeks. The main variables used to compare effectiveness were the increase in serumhemoglobin levels during treatment and the percentage of patients with hemoglobin values 120 g/l.RESULTS: The differences in maximum hemoglobin values achieved at baseline and during the study period,and those between the final and baseline hemoglobin values were similar in the 3 groups. The percentageof patients with hemoglobin values 120 g/l during and at the end of treatment was equivalentfor the group receiving epoetin alpha 10,000 IU three times per week and darbepoetin alpha 150 μg perweek. However this parameter war inferior for the group treated with darbepoetin alpha 500 μg every 3weeks.CONCLUSIONS: Epoetin alpha 10,000 IU 3 times per week was found to be as effective as darbepoetinalpha 150 μg per week in all the studied parameters, while darbepoetin alpha 500 μg every 3 weekswas not in one of them

Estudio de dos cohortes de pacientes para evaluar el índice de resistencia a epoetina alfa y a darbepoetin alfa en pacientes en hemodiálisis crónica / Resistance index to epoetin alfa and to darbepoetin-alfa in chronic hemodialysis patients: a cohort study

La efectividad de la respuesta en la estimulación eritropoyética se puede expresar por el índice de resistencia (IR) a los agentes estimuladores de la eritropoyesis, que expresa la relación entre la dosis administrada del agente y las concentraciones de hemoglobina mantenidas. El IR de una población en hemodiálisis se relaciona con una serie de parámetros clínicos y bioquímicos de la hemodiálisis, como la concentración de albúmina, la proteína C reactiva (PCR), el índice de la masa corporal (IMC) y el Kt/V y se presenta, por tanto, como un índice de valoración de un conjunto muy importante de parámetros que expresan la patología comórbida de los pacientes y la calidad del tratamiento recibido. Una proporción considerable de pacientes en hemodiálisis crónica presentan una resistencia relativa o respuesta subóptima a la eritropoyetina recombinante humana (rHuEPO), por lo que precisan dosis elevadas de esta proteína para alcanzar unas concentraciones de hemoglobina superiores a los 11 g/dl. Darbepoetin alfa es una nueva proteína estimuladora de la eritropoyesis con un perfil farmacocinético caracterizado por una semivida mucho más prolongada que la de rHuEPO y una mayor actividad biológica in vivo, permaneciendo mucho más tiempo en plasma a concentraciones clínicamente eficaces en comparación con rHuEPO. El presente estudio evalúa el resultado de cambiar la administración de epoetina alfa a darbepoetin alfa sobre la efectividad y la calidad del tratamiento, determinadas mediante el IR, en pacientes en hemodiálisis que requieren un tratamiento a dosis altas (> 10.000 UI/sem) o bajas (< 4.000 UI/sem) de epoetina alfa por vía i.v., en comparación con un grupo control que siguió recibiendo epoetina alfa. En los dos grupos de pacientes que cambiaron a darbepoetin alfa, se registró una disminución del IR y de la dosis necesaria de darbepoetin alfa con relación a la dosis equivalente en el momento de la conversión, que no fue observada en los grupos control. En el grupo que precisó dosis altas, el IR a darbepoetin alfa (IRD) al final del estudio (semana 24), disminuyó un 23,9% respecto al IR a epoetina alfa (IRE) en el momento de la conversión (semana 0), una disminución que fue estadísticamente significativa (p < 0,01). De forma similar, en el grupo tratado con dosis bajas que cambió a darbepoetin alfa, se registró una disminución del IRD al final del estudio del 13,4% respecto al IRE en el momento de la conversión (p = NS). En ambos grupos control el IRE final aumentó respecto al inicial. Las concentraciones de hemoglobina se mantuvieron estables en todos los grupos a lo largo de todo el período de seguimiento del estudio, con unos valores medios que oscilaron entre los 11,5 y los 13,3 g/dl. Los valores de la PCR al final del estudio (semana 24) mostraron una relación significativa con las concentraciones de albúmina (p < 0,001). En conclusión, la conversión de epoetina alfa a darbepoetin alfa en pacientes en hemodiálisis tuvo como resultado una mejoría significativa del IR al tratamiento en los pacientes con mayores necesidades de AEE

The effectiveness of the erythropoietic response can be evaluated using the resistance index (RI) to erythropoietic agents (EA) that measures the relationship between the dose administered and the hemoglobin levels attained. In a hemodialysis population, the RI is associated with several clinical and biochemical parameters, such as albumin levels, C-reactive protein (CRP), body mass index (BMI) and Kt/V. This index therefore reflects an important group of parameters that indicate comorbidities and measures the effectiveness of the treatment received. A substantial proportion of chronic hemodialysis patients show a relative resistance to human recombinant erythropoietin (rHuEPO) and require high doses to reach hemoglobin levels above 11 g/dl. Darbepoetin alfa is a new erythropoietic agent with a longer half-life than rHuEPO and greater biological activity in vivo. Furthermore, it remains at clinically effective plasma levels for much longer than rHuEPO. This study evaluated the effect on RI of switching from epoetin alfa to darbepoetin alfa in hemodialysis patients requiring iv rHuEPO at either high (> 10,000 UI/w) or low (< 4,000 UI/w) doses, compared to a control group receiving epoetin alfa. Unlike the control group, both groups of patients who switched to darbepoetin alfa showed a reduction in RI and a progressive reduction in the dose required of darbepoetin alfa with respect to the equivalent dose at treatment conversion. In the group requiring high doses, darbepoetin alfa RI (DRI) at week 24 was a significant 23.9% lower than epoetin alfa RI (ERI) at conversion (week 0) (p < 0.01). In the group requiring low doses, DRI at week 24 was 13.4% lower than the ERI at conversion (p = NS). In both control groups, ERI at week 24 was higher than ERI at week 0. All groups showed stable hemoglobin levels across the study, with mean levels between 11.5 and 13.3 g/dl. CRP at week 24 was significantly related to albumin levels (p < 0.001). In conclusion, switching hemodialysis patients from epoetin alfa to darbepoetin alfa was associated with a significant improvement in RI in the group of patients with high doses of EA, which we consider to be an important indicator of the effectiveness and quality of the treatment administered

Once-weekly dose of epoetinum alfa in cancer patients with anemia receiving radiotherapy

Introduction. Anaemia is present in 30%-90% of all patients with cancer, and its origin is multifactorial. Human recombinant erythropoietin has been shown to be useful in treating anemia in patients with cancer. The aim of this study was to evaluate the effectiveness of treatment of anaemia with epoetin alfa (EPO) given as a single weekly dose, and its repercussions on quality of life (QoL). Materials and methods. From January to October 2002, a total of 139 patients referred to our service for radiotherapy (RT) had anemia and received treatment with EPO as a single weekly dose of 40,000 IU subcutaneously, with oral iron supplement. If haemoglobin (Hb) values after 1 month of treatment did not increase by >=1 g/dl, the dose was increased to 60,000 IU/week. Treatment with EPO ended when Hb values reached >=14 g/dl or one month after the end of RT regardless of Hb values. QoL was evaluated with the Functional Assessment of Cancer Therapy-Anaemia subscale (FACT-An) and the Cancer Linear Analogue Scale (CLAS). Results. Mean Hb at the start of treatment with EPO was 11.49 ± 1.08 g/dl, and the mean value at the end of treatment was 14.52 ± 1.41 g/dl (p < 0.001). The mean increase in Hb was 2.97 ± 1.65 g/dl. Mean duration of treatment was 7.13 ± 2.91 weeks. In 11 patients (7.9%) the dose was increased after 4 weeks. In 84 patients (60.4%) EPO treatment was implemented before the commencing of RT. Mean Hb values in this group was 11.34 ± 1.11 g/dl at the start of EPO treatment, 12.69 ± 1.56 g/dl at the start of RT, 13.96 ± 1.54 g/dl at the end of RT and 14.68 ± 1.3 g/dl at the end of EPO treatment (p < 0.001). In 55 patients (39.6%) anaemia developed during RT and, therefore, EPO treatment was implemented after commencing of RT. In this group the mean Hb values were 12.29 ± 1.6 g/dl at the start of RT, 11.72 ± 1.01 g/dl at the start of EPO treatment, 13.97 ± 1.53 g/dl at the end of RT and 14.28 ± 1.54 g/dl at the end of EPO treatment (p < 0.001). Hemoglobin levels at the start of EPO were lower in patients who commenced EPO before RT (p < 0.05). In 60 patients who received combined RT and chemotherapy, mean Hb values were 11.42 ± 1.16 g/dl at the start of EPO and 13.98 ± 1.55 g/dl at the end of EPO (p < 0.005). In 75 patients who had received RT alone, the mean Hb values was 11.53 ± 1.05 g/dl at the start of EPO and 14.98 ± 1.17 g/dl at the end of treatment (p < 0.001). Patients treated with RT alone had higher Hb levels at the end of RT and at the end of EPO treatment than did patients who had received combined treatment (p < 0.005). The duration of EPO treatment was shorter in the group treated with RT alone than in the combined treatment group (6.41 ± 2.99 weeks versus 7.96 ± 2.67 weeks; p < 0.005). No significant differences were observed in FACT-An and CLAS scores at the beginning and the end of the study. Conclusions. Treatment with epoetin alfa as a single weekly dose significantly increased Hb levels in patients with cancer who were undergoing radiotherapy. The response was greater in patients treated with radiotherapy alone than in those receiving combined therapy. The duration of EPO treatment was shorter in the group treated with radiotherapy alone than in the combined treatment group