Administration Of Epoetin Alfa Research Articles

Development of an In Vivo Model To Assess Factors That May Stimulate the Generation of an Immune Reaction to Epoetin Alfa.

The incidence of pure red cell aplasia (PRCA) in patients with chronic kidney disease associated with the subcutaneous (sc) administration of epoetin alfa (EPREX®) began to increase in 1998. As part of an intensive investigation into the reasons for this increase, an in vivo model was developed to assess the ability of potential causative factors to stimulate an immune response to recombinant human erythropoietin (rHuEPO). Due to species differences in protein sequence and as well as antigen processing and/or presentation, animal models cannot fully predict immunogenicity in humans. However, changes in relative immunogenicity have been readily detected in animal models. Moreover, transgenic animals have been utilized to negate the effects due to sequence differences between species. The EPO sequence is highly homologous between mouse and man. We found it difficult to generate anti-EPO antibodies in both human EPO transgenic mice and two normal mouse strains (Balb/c and BD-F1). To mitigate the complicating factors associated with the transgenic model (e.g. difficulty breeding, improper regulation of EPO production), normal mouse strains were selected for the development of animal models. Mice were injected sc with rHuEPO weekly for 4–6 weeks. Serum samples were analyzed 1–2 weeks following the last injection to ensure complete clearance of the injected protein. Serum samples were screened by an ELISA and/or by a surface plasmon resonance (BIAcore) method. In animals injected with rHuEPO alone, anti-EPO antibodies were either absent or present at very low levels. The addition of an adjuvant to the immunization protocol was able to boost both the rate of occurrence and titer of the immune response and resulted in the generation of anti-EPO antibodies that, in most cases, recognized both human and mouse EPO. Some of the mice exhibited a dramatic reduction in hematocrit, suggesting that the anti-EPO antibodies neutralized endogenous EPO. The development of an anti-EPO antibody response in humans is an extremely rare event that cannot be reproduced in an animal model without significant manipulation of the system (e.g. use of an adjuvant with doses of EPO considerably higher than therapeutic levels). Nevertheless, the fact that anti-EPO antibodies can develop with an appropriate immunization protocol allows for this model to be used to evaluate factors that may potentiate an immune response to rHuEPO.

The Erythropoietin Receptor and Its Expression in Tumor Cells and Other Tissues

Erythropoietin (EPO) is the primary regulator of erythropoiesis, stimulating growth, preventing apoptosis, and promoting differentiation of red blood cell progenitors. The EPO receptor belongs to the cytokine receptor superfamily. Although the primary role of EPO is the regulation of red blood cell production, EPO and its receptor have been localized to several nonhematopoietic tissues and cells, including the central nervous system (CNS), endothelial cells, solid tumors, the liver, and the uterus. The presence of EPO receptors and the possibility of EPO signaling in these tissues and cells have led to numerous studies of the effects of EPO at these sites. In particular, expression of EPO and the EPO receptor in cancer cells has generated much interest because of concern that administration of recombinant human erythropoietin (rHuEPO) to patients with breast and other cancer cells expressing the EPO receptor may promote tumor growth via the induction of cell proliferation or angiogenesis. However, evidence supporting a growth-promoting effect has been inconclusive. Moreover, several preclinical studies have shown a beneficial effect of EPO on delaying tumor growth. Further, it is conceivable that increased expression of EPO could reduce tumor hypoxia and ameliorate the deleterious effects of hypoxia on tumor growth, metastasis, and treatment resistance. On the other hand, EPO has also been shown to produce an angiogenic effect in vascular endothelial cells in vitro. However, there is no evidence that these effects occur in vivo to promote tumor growth. EPO and EPO receptors are expressed in neural tissue, and they are upregulated there by hypoxia. Animal studies have shown that administration of epoetin alfa (an rHuEPO) reduces tissue injury due to ischemic stroke, blunt trauma, and experimental autoimmune encephalomyelitis. These findings suggest that epoetin alfa may provide a therapeutic benefit in patients with stroke, trauma, epilepsy, and other CNS-related disorders. Clearly, further study of EPO and the EPO receptor in nonhematopoietic tissue is warranted to determine the potential therapeutic usefulness of rHuEPO as well as to determine the signaling pathway responsible for its effect in vivo.

RHuEPO and Treatment Outcomes: The Preclinical Experience

The presence of hypoxic areas is a common feature of solid tumors and has been associated with decreased sensitivity of the tumors to radiation therapy and oxygen-dependent chemotherapeutic agents, as well as worsened outcomes, including survival. Anemia is also common in cancer patients and is believed to contribute to tumor hypoxia. Thus, the rationale exists for administering recombinant human erythropoietin (rHuEPO, epoetin alfa) in an effort to increase hemoglobin levels, correct anemia, and thereby possibly increase the sensitivity of tumors to standard cancer treatment and improve patient outcomes. The results of several preclinical studies that examined the impact of anemia prevention by rHuEPO on tumor sensitivity to radiation therapy in rodent models of cancer showed that induction of anemia increased hypoxia in tumor cells and that correction of anemia with rHuEPO could improve tumor oxygenation. Further studies in rodent models showed significantly delayed tumor growth in both irradiated mice and irradiated rats treated with rHuEPO. In those studies, the increased radiosensitivity observed was believed to be due to improved tumor oxygenation following the correction of anemia. Similarly, enhancements in chemosensitivity were found in rHuEPO-treated rodent models. In the chemosensitivity studies, as in the radiosensitivity studies, the therapeutic benefit obtained was believed to reflect improved tumor oxygenation subsequent to an rHuEPO-related increase in oxygen availability. One study evaluated the potential biologic effects of epoetin alfa on tumor progression using murine myeloma models (MOPC-315 and 5T33 MM). Treatment of MOPC-315 tumor-bearing mice with epoetin alfa induced complete tumor regression in 30%-60% of mice. Regression was found to be tumor specific, and the effect of epoetin alfa was shown to be T-cell mediated. Additionally, epoetin alfa administration prolonged survival and reduced morbidity and mortality in the 5T33 MM tumor model. Those investigators suggested that epoetin alfa may have antitumor activity in addition to its hematopoietic effects. Overall, these preclinical findings suggest that correction of anemia by rHuEPO can increase tumor sensitivity to both radiation therapy and chemotherapy and that epoetin alfa may exert an immunomodulatory effect in multiple myeloma.

Weekly Administration of Epoetin Alfa Improves Cognition and Quality of Life in Patients with Breast Cancer Receiving Chemotherapy

Patients with breast cancer treated with adjuvant chemotherapy experience not only fatigue and menopausal symptoms but also documented cognitive dysfunction and reduced capacity to carry out activities of daily living. The role of epoetin alfa in improving cognition and functional capacity was assessed in a large randomized trial through patient self-reported outcomes. Patients with breast cancer (N = 354, adjuvant and metastatic) undergoing chemotherapy were randomized in a 1:1 ratio to receive epoetin alfa (40,000 IU once weekly) or the standard of care (SOC). Change in patient-reported Health Utilities Index Mark 3 (HUI3) from baseline to week 12 was compared between the epoetin alfa and SOC groups. In addition, correlations between the disease-nonspecific HUI3 utility scale and the cancer-specific quality of life instrument Functional Assessment of Cancer Therapy–Anemia (FACT-An) and Fatigue subscales were assessed. Epoetin alfa treatment significantly improved HUI3 scores compared with patients receiving SOC (P = 0.036). Three subscales within HUI3 were also significantly better for epoetin alfa–treated patients (emotion, P = 0.048; ambulation, P = 0.048; and cognition, P = 0.02). Moreover, a strong correlation (P = 0.0001) exists between the disease-nonspecific utility scale HUI3 and the disease-specific FACT-An and FACT-Fatigue scales in terms of overall scores and score changes. The findings of the study demonstrate for the first time in patients with breast cancer that epoetin alfa significantly enhances functional well-being, which translates into significantly better utility scores. In addition, epoetin alfa also significantly improved cognitive function of women undergoing chemotherapy, and this could have an important impact on their lives from a societal perspective.

Eritropoyetina preoperatoria como estrategia de ahorro de sangre en cirugía ortopédica mayor en pacientes de edad avanzada

Preoperative anemia is a major risk factor for perioperative transfusion in orthopedic surgery and aging is associated with an increased risk for developing anemia. The aim of this study was to compare the efficacy and safety of preoperative epoetin alfa in patients older and younger than 65 years in orthopedic surgery. PATIENTS AHD METHOD: This study involved 75 patients scheduled for total joint arthroplasty who had an hemoglobin level between 100 and 130 g/l. Patients were assigned to receive weekly doses of subcutaneous epoetin alfa (40000 IU) on days -21, -14, -7, -1 before surgery. We tabulated age, weight, gender, baseline analytic parameters, perioperative evolution of the mean hemoglobin level, transfusion, side effects and complications. Fifty-four patients were included in group A (> or = 65 years) and 21 in group B (< 65 years). The two study groups did not differ in terms of demographic characteristics and baseline analysis but differed in age and associated diseases. The preoperative increase in mean hemoglobin level (20 and 18 g/l) and transfusion rate (15% and 14.3%) were similar in both groups. There were no complications associated with the use of epoetin alfa. Preoperative epoetin alfa administration seems to be as effective and safe in patients younger as in those older than 65 years.

A cross-sectional immunosurveillance study of anti-EPO antibody levels in CRF patients receiving epoetin alfa in 5 Ontario renal centers

Background: Epoetin alfa (Eprex*; Johnson & Johnson, Manati, PR) has been used successfully to correct the anemia of chronic renal failure for more than 12 years. Anti-erythropoietin (anti-EPO) antibodies have been reported in a small number of patients, resulting in a blood disorder, pure red cell aplasia (PRCA). To evaluate the utility of a large-scale anti-EPO antibody screening program in patients with chronic kidney disease (CKD) administered epoetin alfa, a study involving 5 large renal centers in southern Ontario, Canada, was conducted. Methods: More than 1,500 hemodialysis, peritoneal dialysis, and predialysis patients were screened for the prevalence of anti-EPO antibodies by means of a radioimmunoprecipitation (RIP) assay. Serum samples were drawn and shipped to PPD Development (Richmond, VA) for the immunoprecipitation assay. Serum EPO levels also were measured. All samples that tested positive or borderline for antibodies were sent to MDS Pharma Services (Montreal, Canada) for the neutralization assay. Results: Of 1,531 samples tested, 1 patient tested low-positive and 3 borderline results were detected by means of RIP. PRCA previously was diagnosed in the patient with the low-positive antibody level; the patient was treated with cyclosporine and currently is being administered epoetin alfa with good response. The 3 patients with borderline antibody results manifested no clinical signs of PRCA. Neutralization assays performed on all 4 serum samples were negative for anti-EPO antibodies. Conclusion: Results from this surveillance study show that the prevalence of antibody to EPO in patients with CKD administered epoetin alfa in 5 Canadian renal centers is low, and the value of a large-scale antibody screening program for PRCA cannot be justified.

Pharmacokinetics (PK) of intravenously (IV) administered epoetin alfa in pediatric patients receiving myelosuppressive chemotherapy

8552 Background: The disposition of epoetin alfa (EPO, PROCRIT®) has not been well characterized in children. Therefore, we evaluated EPO PK in children with malignant solid tumors undergoing myelosuppressive chemotherapy. Methods: Children in this study were treated at a single center, but were enrolled in a multicenter double-blind, placebo controlled study of EPO. Children received IV EPO 600 IU/kg (max dose 40,000 IU) once weekly for 16 weeks. Serial PK studies were conducted after first EPO dose, and after ninth or tenth EPO dose. Plasma samples were obtained prior to EPO injection and at 0.25, 0.5, 1, 3, 6, 8, and 24 hours after EPO. Plasma EPO concentrations were analyzed using an ELISA assay, with a calibration curve ranging from 0.025 to 0.200 IU/mL. A two-compartment model was fit to the data using maximum likelihood estimation (ADAPT II). Results: 13 children were enrolled in the study, of whom 6 (median age 15.2 yrs; range 9.3–18.6 yrs) were randomized to receive EPO. Results from PK studies performed after the first EPO dose (n=6 patients) revealed a median (range) apparent AUC0–24 and clearance (CL) of 70.1 IU/mL*hr (17.29–108.0) and 0.25 L/hr/m2 (0.13–0.87), respectively. The median (range) apparent elimination rate constant (ke) after the first EPO dose was 0.12 h-1 (0.06–0.14). Subsequent PK analysis performed after the ninth or tenth EPO dose in 4 patients showed a median (range) apparent AUC0–24 and CL of 146.2 IU/mL*hr (116.0–172.9) and 0.11 L/hr/m2 (0.02–0.17), respectively. The median (range) apparent EPO ke in these 4 patients was 0.092 h−1 (0.0089–0.11). Conclusions: After multiple EPO doses, an increase in the median apparent EPO AUC0–24 was observed, whereas the median apparent EPO CL decreased by approximately half. The cause of these differences is currently being investigated. Future analyses will relate PK results with pharmacodynamic measures of hematopoeisis and quality of life. Study supported by Ortho Biotech Products, LP, and ALSAC. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen Oncology Ortho Biotech

Pharmacokinetics (PK) of intravenously (IV) administered epoetin alfa in pediatric patients receiving myelosuppressive chemotherapy

8552 Background: The disposition of epoetin alfa (EPO, PROCRIT®) has not been well characterized in children. Therefore, we evaluated EPO PK in children with malignant solid tumors undergoing myelosuppressive chemotherapy. Methods: Children in this study were treated at a single center, but were enrolled in a multicenter double-blind, placebo controlled study of EPO. Children received IV EPO 600 IU/kg (max dose 40,000 IU) once weekly for 16 weeks. Serial PK studies were conducted after first EPO dose, and after ninth or tenth EPO dose. Plasma samples were obtained prior to EPO injection and at 0.25, 0.5, 1, 3, 6, 8, and 24 hours after EPO. Plasma EPO concentrations were analyzed using an ELISA assay, with a calibration curve ranging from 0.025 to 0.200 IU/mL. A two-compartment model was fit to the data using maximum likelihood estimation (ADAPT II). Results: 13 children were enrolled in the study, of whom 6 (median age 15.2 yrs; range 9.3–18.6 yrs) were randomized to receive EPO. Results from PK studies p...

Pharmacokinetics (PK) and pharmacodynamics (PD) of epoetin alfa in cancer patients with anemia receiving cyclic chemotherapy

8203 Background: PK and PD profiles of epoetin alfa for healthy subjects after subcutaneous (SC) administration of epoetin alfa 150 IU/kg 3 times weekly (TIW) or 40,000 IU weekly (QW) have been previously described. This is our first report of PK/PD profiles in anemic cancer patients (pts) receiving chemotherapy (CT). Methods: This was a randomized, open-label, parallel-design, 6-week, multicenter study to determine PK/PD profiles of epoetin alfa 150 IU/kg TIW and 40,000 IU QW in cancer pts. Measurements began when cancer pts received their first dose of epoetin alfa and were scheduled to receive at least 1 cytotoxic CT agent (Day 1). All subjects had a PK profile during Week 1 and an optional profile again at Week 3 (cancer pts not scheduled to receive chemotherapy between Days 15 and 21). Any transfusions were recorded. Results: 29 of 36 cancer pts were evaluable for PK. The 40,000 IU QW regimen had a higher Cmax, higher exposure to epoetin alfa/erythropoietin in serum (in terms of AUC0–7days), and a lo...

Pharmacokinetics (PK) and pharmacodynamics (PD) of epoetin alfa in cancer patients with anemia receiving cyclic chemotherapy

8203 Background: PK and PD profiles of epoetin alfa for healthy subjects after subcutaneous (SC) administration of epoetin alfa 150 IU/kg 3 times weekly (TIW) or 40,000 IU weekly (QW) have been previously described. This is our first report of PK/PD profiles in anemic cancer patients (pts) receiving chemotherapy (CT). Methods: This was a randomized, open-label, parallel-design, 6-week, multicenter study to determine PK/PD profiles of epoetin alfa 150 IU/kg TIW and 40,000 IU QW in cancer pts. Measurements began when cancer pts received their first dose of epoetin alfa and were scheduled to receive at least 1 cytotoxic CT agent (Day 1). All subjects had a PK profile during Week 1 and an optional profile again at Week 3 (cancer pts not scheduled to receive chemotherapy between Days 15 and 21). Any transfusions were recorded. Results: 29 of 36 cancer pts were evaluable for PK. The 40,000 IU QW regimen had a higher Cmax, higher exposure to epoetin alfa/erythropoietin in serum (in terms of AUC0–7days), and a lower clearance (CL/F) than the 150 IU/kg TIW regimen. Despite differences in concentration–time profiles and overall exposure to epoetin alfa/erythropoietin between the 2 treatment groups, responses as indicated by profiles of changes in PD parameters and their AUC (% reticulocytes, hemoglobin [Hb], and total RBCs) were similar. The AUC of change in Hb in cancer pts over 6 weeks is shown in the table. Conclusions: Epoetin alfa was safe and well tolerated in this study. Despite differences in PK profiles between the 2 regimens, this study indicates that the PD responses to epoetin alfa were similar. Thus, total systemic exposure is not the sole determinant of the PD effects of epoetin alfa. Other factors, such as pattern of exposure or duration of exposure above a critical threshold level, may also contribute to PD effects. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration J & J Pharmaceutical Research & Development, LLC J & J Pharmaceutical Research & Development, LLC; Johnson & Johnson J & J Pharmaceutical Research & Development, LLC; Johnson & Johnson

Supportive treatment for anemic cancer patients.

Anemia in cancer patients is frequent but often underestimated. Anemia affects the health-related quality of life and impacts prognosis and outcome of therapy. Treatment options include the administration of hematopoietic growth factors and red blood cell transfusions. Blood transfusions result in rapid but often transient improvement of anemia. Administration of epoetin or darbepoetin alfa increases hemoglobin levels, decreases blood transfusions, and improves quality of life in patients with cancer. Presently, trials investigate whether treatment of anemic cancer patients with erythropoietin impacts on outcome of chemo- and/or radiotherapy and on overall survival. Oncologists must be aware of the clinical relevance of anemia and offer adequate treatment options to their patients. Supportive treatment of anemic cancer patients presenting anemia-related symptoms should be performed to reduce symptoms in cancer patients and optimize outcome to anticancer therapy.

Epoetin alfa treatment for acute anaemia during interferon plus ribavirin combination therapy for chronic hepatitis C.

Infection with the hepatitis C virus (HCV) remains chronic in 75% of infected individuals, in whom it can cause liver inflammation and progressive fibrosis leading to cirrhosis in 20% of patients. A sustained viral response (SVR) to HCV therapy, i.e. undetectable plasma HCV RNA 6 months after the end of treatment, leads to permanent eradication of the virus in 98.3% of patients. The current treatment of choice is combination therapy with pegylated interferon alfa (PEG-IFN alfa), 2a or 2b, and ribavirin (RBV), which achieves an SVR in 54-56% of patients. In patients with HCV genotype 1, RBV doses of 1000-1200 mg/day are associated with a higher SVR than 800 mg/day (51 vs 40%). However, RBV also causes dose-dependent reversible haemolytic anaemia that, in combination with the myelosuppressive effects of PEG-IFN, results in a mean drop in haemoglobin (Hb) level of 3.7 g/dL within 4 weeks. Conventionally, this acute anaemia has been managed with RBV dose reductions. However, this may result in a decreased SVR rate. Alternatively, this anaemia can be managed with administration of epoetin alfa at 40 000 IU once weekly. In a randomized placebo-controlled trial, treatment with epoetin alfa has been shown to raise Hb levels and maintain RBV doses. Furthermore, the increase in Hb level was associated with improved quality of life. Anaemia in patients treated with interferon plus RBV combination therapy can be managed effectively and safely with once weekly epoetin alfa without sacrificing optimal dosing of RBV.

Conversion of Chronic Hemodialysis Patients from Erythropoietin Alfa to Darbepoetin Alfa

Fourteen hemodialysis patients were selected to receive once every other week darbepoetin alfa in substitution for weekly subcutaneously administered epoetin alfa. All patients included in the analysis were male veterans over the age of 18 on established and unchanging doses of subcutaneous erythropoietin alfa and on hemodialysis for at least 3 months. All patients had sufficient iron stores, defined as serum ferritin concentrations of greater than 100 mcg/L. Patients were converted to darbepoetin alfa using the manufacturer's conversion chart. Doses of darbepoetin alfa were adjusted to maintain a hemoglobin concentration greater than 11 to 12 g/dL and a hematocrit greater than 33% to 36%. Patients were followed for 4 months and evaluated for efficacy. Hemoglobin, hematocrit, and serum ferritin levels were measured at baseline and repeated every month. Among the 12 patients completing the study 12 dose increases of darbepoetin alfa were needed. Switching these 12 patients from erythropoietin alfa to darbepoetin alfa was projected to increase acquisition cost by more than $36,000, assuming that these patients remained on their current doses of darbepoetin alfa for 1 year. The authors concluded that darbepoetin alfa should not be used in patients with anemia caused by chronic renal failure who require hemodialysis until further studies support this use.

Blood Transfusions and Postoperative Recovery in Orthopedic Surgery. The European Eprex Surgery Trial

SUMMARYThis trial compared the effect of preoperative administration of epoetin alfa (EPO) and best standard of care (BSC) on transfusion rate and its impact on postoperative recovery in a daily life setting. Hemoglobin (Hb) concentrations, transfusions, time to ambulation, hospitalization time, infections, and safety parameters were evaluated in orthopedic surgery patients with preoperative Hb values 10–13 g/dL from study entry until 4–6 weeks after surgery (on‐treatment: 460 patients EPO, 235 BSC). Mean Hb values (not different at baseline) were higher in the EPO group than in the BSC group (p &lt; 0.05) from the day of surgery until the end of the observation period. Transfusion rate was 12% in the EPO group vs. 46% in the BSC group (p &lt; 0.05). No significant relation was detected between treatment and postoperative recovery (hospitalization time, time to ambulation, infection rate), probably due to the small number of transfused patients in the EPO group. Hospitalization time and time to ambulation were, however, longer in transfused than in nontransfused patients (p &lt; 0.05). Postoperative infections occurred in 12.9% and 8.9% of transfused and nontransfused patients, respectively (NS). Side effects in both groups were comparable. We conclude that epoetin alfa significantly increases Hb in the perioperative period in mildly to moderately anemic patients, with a significant reduction of allogeneic blood transfusions. Patients exposed to allogeneic blood transfusion require a longer hospitalization. The number of transfusions in this study was too limited to confirm former observations on reduction of postoperative infections.

Impact of epoetin alfa on clinical end points in patients with chronic renal failure: A meta-analysis

Numerous randomized, controlled trials have demonstrated that recombinant human erythropoietin (rHuEPO, epoetin alfa) significantly raises hemoglobin levels, reduces transfusion requirements, and improves quality of life in anemic patients with chronic renal failure. However, this accumulation of data has yet to be systematically examined. The objectives of this meta-analysis were to quantify the effects of epoetin alfa on clinical efficacy, quality of life, hospitalizations, and transfusions by collecting and analyzing the published body of evidence. Sixteen published studies fulfilled all inclusion criteria and were subjected to data extraction. Data specifically related to hemoglobin and/or hematocrit levels, quality-of-life measurements, number and length of hospitalizations, and number of blood transfusions were then pooled across studies using a random effects meta-analysis. Simple combined estimates of the preselected variables were calculated, and adjusted estimates were made using meta-regression. Baseline hemoglobin levels (<8 g/dL) increased substantially (40% to 50%) after epoetin alfa administration to a nonanemic state (Hb >11 g/dL) for the pooled study group. Substantial improvements (10% to 70%) were observed for all measures of quality of life. In addition, patients who received epoetin alfa had substantial reductions in hospitalization rate, hospital length of stay, transfusion rate, and number of units transfused. This meta-analysis strongly suggests that epoetin alfa therapy for patients with chronic renal failure provides important clinical and quality-of-life benefits while substantially reducing hospitalizations and transfusions.

Epoetin Alfa 60,000 U Once Weekly Followed by 120,000 U Every 3 Weeks Increases and Maintains Hemoglobin Levels in Anemic Cancer Patients Undergoing Chemotherapy

Epoetin alfa administered s.c. three times weekly or once weekly increases hemoglobin (Hb) levels, decreases transfusion requirements, and improves quality of life in anemic cancer patients receiving chemotherapy. This study assessed the feasibility of using higher initial doses of once-weekly epoetin alfa followed by less frequent maintenance doses to increase and then maintain adequate Hb levels in this population. In this open-label, nonrandomized, pilot study, anemic (baseline Hb < or = 11 g/dl) cancer patients undergoing chemotherapy received initial doses of epoetin alfa of 60,000 U s.c. once weekly to increase Hb levels by at least 2 g/dl, followed by 120,000 U s.c. every 3 weeks to maintain Hb levels. The maximum treatment duration was 24 weeks. The mean baseline Hb level was 10.1 +/- 0.8 g/dl (n = 20). Once-weekly dosing resulted in mean Hb level increases of 1.0 +/- 1.1 g/dl by week 4 and 2.9 +/- 1.9 g/dl by week 8; 86% and 79% of patients evaluable at week 8 and week 12, respectively, demonstrated increases of at least 2 g/dl (target Hb level of > or = 12 g/dl). Thirteen patients (65%) received at least one maintenance dose; the mean Hb level increased from 12.8 +/- 1.1 g/dl before starting maintenance therapy to 13.3 +/- 1.4 g/dl at the last maintenance week. Both dosage regimens were well tolerated. Once-weekly epoetin alfa at a dose of 60,000 U effectively increased Hb levels by week 8; 86% of patients achieved rises of at least 2 g/dl or Hb levels > or = 12 g/dl. Moreover, epoetin alfa at doses of 120,000 U every 3 weeks maintained or increased Hb levels. Results from this pilot study suggest that higher initial once-weekly dosing of epoetin alfa followed by less frequent maintenance dosing appears to be feasible for treating anemia in cancer patients undergoing chemotherapy. Further evaluation of these and other epoetin alfa dosage regimens is warranted.

Epoetin alfa has potential efficacy in central nervous system disorders

Recombinant human erythropoietin (rHuEPO, epoetin alfa) is a 165-amino acid glycoprotein that has been shown to initiate response to hypoxia and is most widely known for its efficacy in the treatment of a variety of anemias. A series of experiments were conducted using rodent models to investigate the ability of systemically administered epoetin alfa to cross the blood-brain barrier (BBB) and affect the outcome of hypoxia and injury in the central nervous system. Results demonstrated that endogenous erythropoietin (EPO) and EPO receptors are expressed around animal brain capillaries and that systemically administered epoetin alfa crossed the BBB. The epoetin alfa group experienced significantly reduced ( P <0.01) tissue damage in an ischemic stroke model when the study drug was administered 24 h before inducing stroke compared with control animals. Significant protective effects of epoetin alfa persisted when epoetin alfa was administered up to 6 h poststroke ( P <0.05). Similarly, epoetin alfa reduced trauma-related brain injury when administered 24 h prior to and up to 6 h after blunt trauma when compared with the control group. The volume of tissue necrosis was significantly greater in control animals compared with those that received epoetin alfa ( P <0.05). In addition, these studies led to the postulate that epoetin alfa may also have an effect on nervous system inflammation. This was confirmed using an experimental auto-immune encephalomyelitis model, where rats were shown to have significantly delayed onset ( P <0.01) and reduced severity ( P <0.05) of symptoms after treatment with epoetin alfa. Other studies demonstrated that epoetin alfa had an effect on the latency and severity of seizures and significantly increased ( P <0.0002) survival versus controls when mice were exposed to the neurotoxin kainate (used to induce seizures). These findings suggest future potential therapeutic uses for epoetin alfa beyond its anemia-related effects.

Central nervous system frontiers for the use of erythropoietin.

Recombinant human erythropoietin (r-HuEPO; epoetin alfa) is well established as safe and effective for the treatment of anemia. In addition to the erythropoietic effects of endogenous erythropoietin (EPO), recent evidence suggests that it may elicit a neuroprotective effect in the central nervous system (CNS). Preclinical studies have demonstrated the presence of EPO receptors in the brain that are up-regulated under hypoxic or ischemic conditions. Intracerebral and systemic administration of epoetin alfa have been demonstrated to elicit marked neuroprotective effects in multiple preclinical models of CNS disorders. Epoetin alfa has also been shown to prevent the loss of autoregulation of cerebral blood flow in a model of subarachnoid hemorrhage. The mechanisms of EPO-induced neuroprotection include prevention of glutamate-induced toxicity, inhibition of apoptosis, anti-inflammatory effects, antioxidant effects, and stimulation of angiogenesis. Collectively, these findings suggest that epoetin alfa may have potential therapeutic utility in patients with ischemic CNS injury.

Anemia in the treatment of hepatitis C virus infection.

Hepatitis C virus (HCV) infection is a significant worldwide health care problem. Nearly one-third of all patients infected with human immunodeficiency virus (HIV) are coinfected with HCV. Compared with HIV-monoinfected persons, coinfected individuals experience more rapid progression of fibrosis and higher incidence of cirrhosis and death as a result of liver disease. Treatment for HCV infection includes ribavirin (RBV) plus interferon alfa (IFN-alpha) or pegylated IFN, a combination treatment associated with anemia that may require RBV dose reduction or discontinuation. IFN-RBV-associated anemia is more profound among coinfected patients, who have a high prevalence of pretreatment anemia and may also be taking other medications causing anemia. Epoetin alfa administration to HCV-infected patients with IFN-RBV-related anemia can significantly increase hemoglobin levels and maintain significantly higher RBV doses compared with patients treated with RBV dose reduction alone. Higher RBV doses and adherence to HCV therapy have been associated with higher sustained virologic response (SVR) rates. Maintenance of RBV dose with epoetin alfa may improve adherence, thereby affecting SVR.

Chemotherapy-Induced Cognitive Dysfunction: A Clearer Picture

Chemotherapy-associated cognitive dysfunction occurs in a subset of patients treated with adjuvant chemotherapy. Recent data suggest that development of chemotherapy-related anemia predisposes patients to cognitive dysfunction. Endogenous erythropoietin (EPO) is well recognized for its central role in erythropoiesis, and recombinant human EPO (epoetin alfa) is established as a safe and effective treatment for chemotherapy- related anemia. Treatment with epoetin alfa also improves health-related quality of life in anemic cancer patients undergoing chemotherapy, and several controlled studies have documented increases in quality-of-life scores correlated with increases in hemoglobin. Erythropoietin also plays a role in neuroprotection, presumably by activation of antiapoptotic genes. Erythropoietin and its receptor are expressed in neural cells of the human brain, and their expression is upregulated after hypoxic or ischemic injury. In animal models, systemic administration of epoetin alfa protects against such neural injury. Ongoing and future studies will determine whether epoetin alfa can provide neuroprotection with respect to the development of cognitive dysfunction in patients undergoing adjuvant chemotherapy treatment for breast cancer.