Once-monthly administration of darbepoetin alfa for the treatment of patients with chronic heart failure and anemia: a pharmacokinetic and pharmacodynamic investigation

In patients with chronic heart failure (CHF), anemia is associated with more severe symptoms and worse prognosis. Erythropoiesis-stimulating proteins (ESPs) increase hemoglobin and may be of therapeutic benefit. We investigated the pharmacokinetics and pharmacodynamics of the long-acting ESP, darbepoetin alfa, administered on 2 occasions 1 month apart to 30 healthy subjects and 33 patients with symptomatic CHF and anemia (hemoglobin相似文献   

Development and evaluation of a population pharmacokinetic-pharmacodynamic model of darbepoetin alfa in patients with nonmyeloid malignancies undergoing multicycle chemotherapy

Anemia is frequently observed in patients undergoing chemotherapy. Administration of darbepoetin alfa, a recombinant erythropoiesis-stimulating agent that has longer residence time than endogenous erythropoietin, to patients with chemotherapy-induced anemia (CIA) increases mean hemoglobin concentration, reduces risk of red blood cell transfusions, and improves patient-reported outcomes. A pharmacokinetic/pharmacodynamic (PkPd) model was developed using data from patients with nonmyeloid malignancies and CIA who were receiving darbepoetin alfa. A 2-compartment Pk model with linear elimination described the Pk data obtained in 140 CIA patients after intravenous and subcutaneous (s.c.) doses of 2.25 microg/kg every week and s.c. doses of 6.75 microg/kg every 3 weeks. The population typical values of key Pk parameters were clearance, 2010 mL/day; steady-state volume of distribution, 3390 mL; and bioavailability, 44.3%. A modified indirect response model, wherein serum concentrations stimulated the production of hemoglobin through an Emax-type equation, described the hemoglobin levels after s.c. doses of 0.5 microg/kg every week to 15 microg/kg every 3 weeks in 573 CIA patients. The estimated incremental maximum stimulation of hemoglobin production was 43.7% and darbepoetin alfa serum concentration at half-maximal stimulation was 3.68 ng/mL. The impact of covariates (body weight and platinum-containing chemotherapy) on the PkPd response was evaluated based on point and interval estimates of parameters, rather than through stepwise hypothesis testing. The final PkPd model adequately predicted hemoglobin response in a test data set, thereby confirming the predictive capability of the model. Based on simulations, it was not possible to categorize the influence of any covariate as clinically important.     

Pharmacokinetics of darbepoetin alfa after intravenous or subcutaneous administration in patients with non-myeloid malignancies undergoing chemotherapy

BACKGROUND AND OBJECTIVE: The pharmacokinetics of darbepoetin alfa after intravenous (IV) administration in the oncology setting have not been previously reported. The objective of this study was to evaluate the pharmacokinetics of IV or subcutaneous (SC) darbepoetin alfa in patients with non-myeloid malignancies undergoing multicycle chemotherapy. METHODS: Fifty-six patients (haemoglobin 相似文献   

An extended terminal half-life for darbepoetin alfa: results from a single-dose pharmacokinetic study in patients with chronic kidney disease not receiving dialysis

BACKGROUND AND OBJECTIVE: Anaemia is a major and persistent manifestation of chronic kidney disease (CKD) caused by the deficient production of erythropoietin in the kidneys, the prevalence of which is proportional to the deterioration in kidney function. Darbepoetin alfa, an erythropoiesis-stimulating protein, exhibits a lower clearance and longer terminal half-life in serum than recombinant human erythropoietin, thereby allowing for a reduced dosing frequency. A recent study in patients with CKD, using a 4-week sampling period, suggested that the terminal half-life of darbepoetin alfa in serum is longer than that reported in previous studies, which were based on a 1-week sampling period. This study was conducted to characterise the pharmacokinetic profile of a single subcutaneous dose of darbepoetin alfa 1 microg/kg in patients with CKD, using a sampling duration of 4 weeks, which was hypothesised to allow better characterisation of the terminal half-life in serum. METHODS: Twenty patients with CKD not on dialysis, with a calculated glomerular filtration rate of 20-60 mL/min and who had not been treated with erythropoietic agents in the previous 12 weeks, were enrolled into this single-dose, open-label study. Patients received a single subcutaneous dose of darbepoetin alfa (Aranesp) 1 microg/kg on day 1, and blood samples were collected for pharmacokinetic analyses predose, 6 and 12 hours postdose and up to 28 days postdose. Seroreactivity sampling and further safety laboratory tests (clinical chemistry and urinalysis) were also performed. Patients were assessed for adverse events at each study visit. The primary endpoint was characterisation of the terminal half-life following a single subcutaneous dose of darbepoetin alfa 1 microg/kg. RESULTS: The mean terminal half-life in serum of darbepoetin alfa was determined to be 69.6 hours. Peak serum concentrations were reached in a median time of 36 hours postdose, and a mean apparent clearance of 3.51 mL/h/kg was comparable to that observed previously in this patient population. CONCLUSION: Based on an extended sampling schedule of 4 weeks, the terminal half-life of darbepoetin alfa was approximately 70 hours. This is longer than the 48.8 hours reported previously in patients with CKD on dialysis. These data suggest that the pharmacokinetic properties of darbepoetin alfa make this erythropoietic agent well suited to an extended dosing regimen.     

Population pharmacokinetics of darbepoetin alfa in haemodialysis and peritoneal dialysis patients after intravenous administration

AIMS: To characterize the pharmacokinetics of darbepoetin alfa and covariate relationships in haemodialysis (HD) and peritoneal dialysis (PD) patients. METHODS: Data were collected from 131 (63 HD and 68 PD) patients who received darbepoetin alfa intravenously. A total of 917 serum concentrations were available. The data were analysed by nonlinear mixed effect modelling using NONMEM with a model including endogenous erythropoietin production. In addition, the final model was evaluated using bootstrap resampling. RESULTS: The selected basic model was a two-compartment model with a combination of additive and the constant coefficient of variation error models. The significant covariates were weight (WT) for clearance (CL) and the volume of central compartment (V(1)), and the dialysis technique (DIA) for V(1). The typical values of CL and V(1) were 0.0807 l h(-1) and 2.51 l, respectively. V(1) in PD patients was 17% higher than in HD patients. With the introduction of WT in CL and WT and DIA in V(1), interindividual variability decreased from 27.1% to 20.6% in CL and from 29.1% to 21.8% in V(1). The mean parameter estimates from the bootstrap datasets were similar to those from the original dataset. Evaluation by bootstrapping showed that the final model was stable. CONCLUSIONS: The results of the present analysis suggest no dosage regimen change is warranted for darbepoetin alfa in HD and PD patients over the range of distribution of covariates included in this study.     

Evaluation of the US Oncology Network's recommended guidelines for therapeutic substitution with darbepoetin alfa 200 microg every 2 weeks in both naïve patients and patients switched from epoetin alfa

STUDY OBJECTIVE: To evaluate the efficacy of darbepoetin alfa 200 microg subcutaneously every 2 weeks after therapeutic substitution for epoetin alfa. DESIGN: Retrospective multicenter chart review. SETTING: Three US Oncology-affiliated outpatient sites. PATIENTS: Three hundred thirty anemic patients with nonmyeloid malignancies, of whom 174 had been treated previously with epoetin alfa (switched group) and 156 had not been treated recently with epoetin alfa (naive group). INTERVENTIONS: Therapeutic substitution with darbepoetin alfa was started according to the US Oncology Pharmacy and Therapeutics Committee's recommended dosing guidelines: anemic patients with cancer received a starting dosage of darbepoetin alfa 200 microg every 2 weeks regardless of whether or not they had previously received epoetin alfa. Hematologic and darbepoetin alfa usage data were abstracted from consecutive medical records dated from May 2002-March 2003. MEASUREMENTS AND MAIN RESULTS: Median exposure to darbepoetin alfa was 10 weeks (25th quartile 6 wks, 75th quartile 17 wks) and 10 weeks (25th quartile 5 wks, 75th quartile 18 wks) for the naive and switched groups, respectively. The week before the switch to darbepoetin alfa, the 174 patients receiving epoetin alfa were administered the following weekly doses: less than 40,000 U (9%), 40,000 U (50%), or 45,000-90,000 U (41%). Mean hemoglobin level increased from baseline (wk 0) in both the naive and switched groups. The proportion of patients receiving a red blood cell transfusion in the darbepoetin alfa treatment phase was low (15% in each group). No variation in transfusion rates was observed across weight categories in patients who received a fixed dosage of darbepoetin alfa. Darbepoetin alfa was well tolerated. A detailed usage algorithm was validated by these results and is being used in these three US Oncology-affiliated practices. CONCLUSION: A darbepoetin alfa starting dosage of 200 microg subcutaneously every 2 weeks administered according to US Oncology-recommended dosing guidelines is effective in treating chemotherapy-induced anemia in both epoetin alfa-naive patients and those switched from epoetin alfa.     

Utilization of darbepoetin alfa and epoetin alfa for chemotherapy-induced anemia.

PURPOSE: The patterns of use and effectiveness of therapy with darbepoetin alfa and epoetin alfa for chemotherapy-induced anemia (CIA) in hospital outpatient and community settings were evaluated. METHODS: Data were collected from medical charts at 65 oncology clinics in hospital outpatient and community settings for consecutive patients who received the first dose of either darbepoetin alfa or epoetin alfa between August 1, 2002, and February 15, 2003, and were to have had 12 weeks of follow-up data. RESULTS: Data from the charts of 3123 patients were abstracted. Of these patients, 2785 were treated with only one erythropoietic agent (1444 with darbepoetin alfa and 1341 with epoetin alfa) and were included in the analysis. The most common initial dosage of darbepoetin alfa was 200 microg every two weeks (61% of darbepoetin alfa recipients), and the most common initial dosage of epoetin alfa was 40,000 units weekly (72%). With these regimens, the dosage was escalated for 22% of darbepoetin alfa recipients and 23% of epoetin alfa recipients at a median of six weeks after the initial dose. The mean change from baseline in hemoglobin concentration after 12 weeks of therapy was similar for both groups, as was the percent of patients with red-blood-cell transfusions during treatment. CONCLUSION: The most common initial dosage of darbepoetin alfa for CIA was 200 microg every two weeks, and the most common initial dosage of epoetin alfa was 40,000 units weekly. At these dosages, the two agents appear to have similar clinical effectiveness.     

Every-three-week administration of darbepoetin alfa in women with chemotherapy-associated anemia.

PURPOSE: The effectiveness of every-three-week administration of darbepoetin alfa in women with chemotherapy-associated anemia was evaluated. METHODS: Women receiving chemotherapy for gynecological tumors who had a hemoglobin concentration of <10 g/dL were recruited from an obstetrics and gynecology service. Study patients received subcutaneous darbepoetin alfa 6.75 microg/kg, followed by 4.5 microg/kg every three weeks for a total of up to six doses. Hematopoietic response and mean changes in hemoglobin concentrations were evaluated. The Functional Assessment in Cancer Therapy-Anemia (FACT-An) survey was self-administered before and after study completion to evaluate the patients' quality of life. RESULTS: The mean+/-S.D. age and weight for the 14 patients recruited (12 of whom were assessable) were 52.1+/-14 years and 64.6+/-19.8 kg, respectively. The mean initial and maintenance doses were 442 and 301.6 microg, respectively. The overall hematopoietic response was 64.3%, of which 35.7% were complete and 28.6% were partial. Peak response occurred at weeks 9 and 12. The mean+/-S.D. change in hemoglobin concentration was 1.6+/-1.51 g/dL. Treatment failure was predicted by week 9 (n=2). Maintenance doses were withheld if a patient's hemoglobin concentration exceeded 12 g/dL (n=3). The mean+/-S.D. point differential for FACT-An pretreatment and posttreatment scores was 5.8+/-4.71 (n=6). CONCLUSION: Every-three-week administration of subcutaneous darbepoetin alfa produced a complete or partial hematopoietic response in 11 of 14 women with chemotherapy- associated anemia. A quality-of-life indicator generally improved among the 6 patients for whom posttreatment quality-of-life data were available.     

Reengineering clinical operations in a medical practice to optimize the management of anemia of chronic kidney disease

OBJECTIVES: To describe the clinic design, clinical evaluations, and treatment approaches used in a multidisciplinary clinic for management of anemia of chronic kidney disease (CKD), and to evaluate several selected clinical outcomes associated with this approach to anemia management. SETTING: University-affiliated, division of nephrology, outpatient multidisciplinary model CKD clinic headed by a clinical pharmacist. PATIENTS: One hundred sixty-six patients with anemia of CKD who were referred by nephrologists and primary care providers to the multidisciplinary clinic from March 1, 2002-July 31, 2004. MEASUREMENTS AND MAIN RESULTS: Patients received darbepoetin alfa dosed on an every-other-week basis. If patients were already receiving once-weekly recombinant human erythropoietin (r-HuEPO), the darbepoetin alfa dose was calculated by using the darbepoetin alfa package insert conversion table. If patients were na?ve to previous erythropoietic therapy, the darbepoetin alfa dose was either 60 microg or 0.7 microg/kg. The dose and frequency of darbepoetin alfa and oral iron supplements were adjusted to achieve the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (K/DOQI) targets for hemoglobin levels and iron measures. The primary outcome analyzed was the proportion of patients with at least 30 days of treatment who achieved a target hemoglobin level of 11.0 g/dl or greater. Of 128 patients who received at least 30 days of treatment, 100 (78%) attained the hemoglobin level (mean +/- SD 11.7 +/- 7 g/dl). Ninety-nine of 128 patients were originally na?ve to erythropoietic therapy; 77 (78%) of these 99 patients achieved the hemoglobin target in a mean +/- SD of 7.9 +/- 7.5 weeks. These data contrast with the data of 29 patients seen in the year previous to the reengineered clinic process, whereby only 12 (41%) of these comparable patients reached hemoglobin target with r-HuEPO therapy. Of the 77 previously erythropoietic-na?ve patients, 82% were receiving darbepoetin alfa every other week, 14% every 3 weeks, and 4% every 4 weeks at the time the hemoglobin target was achieved. Oral iron administration significantly increased the chance of achieving the K/DOQI targets for hemoglobin and iron. CONCLUSION: Redefining roles and practices of members of a clinical practice and reengineering processes for anemia management were effective in achieving and maintaining target hemoglobin and iron levels.     

Pharmacokinetic and pharmacodynamic modeling of recombinant human erythropoietin after multiple subcutaneous doses in healthy subjects.

A pharmacokinetic and pharmacodynamic (PK/PD) model for recombinant human erythropoietin (Epoetin alfa) in healthy subjects was developed to describe the time profiles of changes in serum Epoetin alfa and the pharmacological responses of percent reticulocytes, total red blood cell counts, and hemoglobin after single and multiple subcutaneous administration of Epoetin alfa. Data used in the development of the model were obtained from a clinical study carried out in healthy volunteers in which Epoetin alfa was administered either as 150 IU/kg three-times-a-week (t.i.w.) or fixed 40,000 IU weekly (q.w.) doses for 4 weeks. A dual-absorption rate model (fast zero-order and slow first-order inputs) with linear disposition kinetics was used to characterize the pharmacokinetics of erythropoietin after subcutaneous administration. A new catenary cell production and lifespan loss model was used to fit the pharmacodynamic data yielding estimates of SC50, Smax, and other pharmacodynamic parameters. Flip-flop kinetics was apparent in the pharmacokinetics as the absorption rate was slower (k(a) = 0.7 day(-1)) than the elimination rate (CL/V(d) = 1.2-9.2 day(-1)). In the pharmacodynamics, an SC50 of 58 mIU/mL was estimated indicating that low serum erythropoietin concentrations were sufficient to produce pharmacological effects. The established PK/PD model predicts similar pharmacological responses of hemoglobin and total red blood cell counts for the 150 IU/kg t.i.w. and 40,000 IU q.w. regimens in healthy subjects.     

Extended-dosage-interval regimens of erythropoietic agents in chemotherapy-induced anemia.

PURPOSE: The safety and efficacy of extended-dosage-interval regimens of erythropoiesis-stimulating agents (ESAs) for managing chemotherapy-induced anemia (CIA) are reviewed. SUMMARY: Anemia is a frequent complication of chemotherapy. The ESAs epoetin alfa and darbepoetin alfa have been shown to safely and effectively manage CIA; comparable outcomes have been demonstrated between epoetin alfa 40,000 units once weekly and darbepoetin alfa 200 microg every two weeks. These commonly prescribed regimens necessitate extra clinic visits by cancer patients receiving cyclic chemotherapy. ESA administration can now often be synchronized with a three-week chemotherapy cycle because of the recent approval of darbepoetin alfa 500 microg every three weeks for CIA. However, in the Phase III trial providing the basis for this new dosage recommendation, more than 70% of patients required a 40% reduction in the dosage, resulting in an average dose of 375 microg every three weeks. The extended-dosage-interval regimens have not been associated with an increase in cardiovascular or thrombotic adverse events. Extended-dosage-interval regimens of epoetin alfa are under investigation and may provide additional alternatives. Synchronizing ESA therapy with scheduled chemotherapy visits would help minimize disruptions for patients and caregivers and improve the use of health care resources. CONCLUSION: Administration of darbepoetin alfa every three weeks offers the convenience of synchronization of treatment with 21-day-cycle chemotherapy in many patients with CIA. Extended-dosage-interval regimens for epoetin alfa are being investigated and show promise.     

Darbepoetin alfa: in patients with chemotherapy-related anaemia

Darbepoetin alfa, novel erythropoiesis stimulating protein closely related to human erythropoietin, has been developed for the treatment of chemotherapy-related anaemia in patients with non-myeloid malignancies. In three 12-week, phase II studies in patients with cancer and chemotherapy-related anaemia, subcutaneous darbepoetin alfa, administered in once-weekly or 2-, 3- or 4-weekly regimens, dose-dependently increased the mean haemoglobin levels. In a randomised, double-blind, phase III study in 320 patients with lung cancer and chemotherapy-related anaemia, recipients of subcutaneous darbepoetin alfa 2.25 micro g/kg once weekly, received red blood cell (RBC) transfusion approximate, equals 2-fold less frequently than placebo recipients (p < 0.001). In the same study, patients receiving darbepoetin alfa also received fewer standard units of RBC for transfusion and had greater haematopoietic response rate than placebo recipients (both p < 0.001). Subcutaneous darbepoetin alfa 2.25 micro g/kg once weekly also reduced patient-reported fatigue (assessed by a quality-of-life questionnaire) [p = 0.019 vs placebo]. black triangle Darbepoetin alfa was generally well tolerated in clinical trials. The most frequent darbepoetin alfa-related adverse events were: body oedema, arthralgia and skin rash.     

Darbepoetin alfa: a novel erythropoiesis-stimulating protein

Darbepoetin alfa is a novel erythropoiesis-stimulating protein developed for the treatment of anemia. It is a hyperglycosylated analog of recombinant human erythropoietin with the same mechanism of action as erythropoietin, but with a three-fold longer terminal half-life after intravenous administration than recombinant human erythropoietin and the native hormone both in animal models and in humans. Clinical studies in patients with chronic renal failure either receiving or not receiving dialysis have shown that darbepoetin alfa is equivalent to recombinant human erythropoietin in terms of increases in hemoglobin concentration, percentage of patients achieving target hemoglobin concentration and average time to reach target hemoglobin concentration, although darbepoetin alfa is administered less frequently (once weekly or every other week). Clinical trials in cancer patients either receiving or not receiving chemotherapy have demonstrated that darbepoetin alfa is safe and effective in alleviating anemia at dose intervals of once every 1, 2 or 3 weeks, and results suggest that it may achieve greater and more rapid responses than recombinant human erythropoietin in cancer patients. Furthermore, an improvement in health-related quality of life has been observed in association with anemia correction using darbepoetin alfa therapy in these patients. Darbepoetin alfa has been approved for intravenous and subcutaneous administration by the European Commission and the FDA for the treatment of anemia in patients with chronic renal failure. Additionally, this product was recently approved by the FDA for the treatment of anemia in patients with nonmyeloid malignancies where anemia is due to the effect of concomitantly administered chemotherapy. The recommended starting dose in chronic renal failure patients is 0.45 microg/kg once weekly for both intravenous and subcutaneous administration, with subsequent titration based on the hemoglobin concentration. In cancer patients, the recommended starting dose is 2.25 microg/kg once weekly by subcutaneous injection and subsequent titration. The adverse event profile of darbepoetin alfa is similar to that of recombinant human erythropoietin in both settings. There are no reports of antibody formation associated with darbepoetin alfa in chronic renal failure patients, and three cases of antibody formation, with neutralizing activity in one of the cases, have been reported in cancer patients. However, no cases of antibody-mediated pure red cell aplasia have been reported. The longer half-life of darbepoetin alfa, together with a similar efficacy and safety profile, confers the clinical advantage over recombinant human erythropoietin of allowing a less frequent dosing (once weekly or every other week versus one to three times weekly in renal patients), thus reducing health-care utilization and probably improving patient compliance.     

Darbepoetin alfa: a review of its use in the treatment of anaemia in patients with cancer receiving chemotherapy

Darbepoetin alfa (Aranesp) is an analogue of recombinant human erythropoietin (rHuEPO) produced using recombinant DNA technology. The high number of sialic acid moieties in darbepoetin alfa results in a prolonged half-life and enhanced in vivo biological activity compared with rHuEPO (as demonstrated in animal studies) and permits a reduction in the frequency of administration.Subcutaneous darbepoetin alfa 2.25 microg/kg once weekly or 500 microg once every 3 weeks (with a provision for dose adjustments) is an effective and well tolerated erythropoietic agent in anaemic patients with cancer receiving chemotherapy. In randomised, controlled clinical trials, the drug increased haemoglobin levels and reduced the need for blood transfusions in patients with various types of nonmyeloid malignancies and also ameliorated anaemia-related fatigue, thereby improving their health-related quality of life (HR-QOL) scores. The once-every-3-weeks dosage regimen provides further convenience by offering the possibility of synchronising its administration with most chemotherapy regimens. Direct comparisons between approved dosages of darbepoetin alfa and other erythropoietic agents have not been conducted. Such comparisons would be very helpful in formulating definitive conclusions about their relative efficacy and cost effectiveness. Darbepoetin alfa provides an effective and well tolerated treatment option for the treatment of anaemia in patients with cancer receiving chemotherapy.     

Population pharmacokinetics of darbepoetin alfa in peritoneal dialysis and non-dialysis patients with chronic kidney disease after single subcutaneous administration

Objective  To characterize the pharmacokinetics of darbepoetin alfa and covariate relationships in chronic kidney disease (CKD) patients after a single subcutaneous administration. Methods  A total of 989 serum concentration recordings from 64 patients were analyzed using NONMEM with a model including endogenous erythropoietin production. The basic and final models were evaluated for stability using bootstrapping. Results  The selected basic model had one-compartment with a combination of the additive and constant coefficient of variation error models for residual variability. The significant covariate was weight for apparent clearance (CL/f) and apparent volume of central compartment (V₁/f). The typical values of CL/f, V₁/f, and absorption rate constant were 0.158 l/h, 13.7 l, and 0.0376/h, respectively. Evaluation by bootstrapping showed that the final model was stable. Conclusion  The present analysis indicated that weight is a significant covariate for CL/f and V₁/f. However, dosage adjustment according to weight is not necessary for subcutaneous administration of darbepoetin alfa in CKD patients.     

Economic evaluation of weekly epoetin alfa versus biweekly darbepoetin alfa for chemotherapy-induced anaemia: evidence from a 16-week randomised trial

INTRODUCTION: A 16-week, open-label, multicentre, randomised trial of weekly epoetin alfa 40 000 units versus biweekly darbepoetin alfa 200microg among 358 patients with solid-tumour cancers and chemotherapy-induced anaemia demonstrated superior haematological outcomes with epoetin alfa. We sought to compare resource use, costs and clinical outcomes between treatment groups and report the results using a cost-consequences framework. METHODS: Pre-specified methods were used to assign costs (US dollars, year 2004-5 values) to medical resources and patient time using a societal perspective. Costs for inpatient care, outpatient care and physician services were based on US Medicare reimbursement rates. Indirect costs assigned to patient time spent receiving study medication were based on the mean hourly wage in the US. In the base-case analysis, the average wholesale price was used to assign costs to medications. Clinical outcomes included all haemoglobin levels and transfusions recorded throughout the trial. Sensitivity analyses were performed to evaluate the impact of different costing methods, cost sources, perspectives and methods to assign haemoglobin values following a blood transfusion. RESULTS: Over a mean follow-up duration of 11.8 weeks, the average cost of study medications and their administration was the single largest component of total costs and was similar between groups (epoetin alfa 5979 US dollars and darbepoetin alfa 5935 US dollars, difference 44 US dollars; 95% CI -590, 692). There were no significant differences in the proportions of patients hospitalised (epoetin alfa 24.6%, darbepoetin alfa 22.0%; p = 0.57). Patients randomised to epoetin alfa experienced more inpatient days, on average, than patients randomised to darbepoetin alfa (2.6 vs 1.6, 95% CI for the difference, 0.07, 2.27). However, with regard to transfusions, patients in the epoetin alfa arm required fewer units of blood than patients in the darbepoetin alfa arm (0.46 vs 0.88, 95% CI for the difference -0.77, -0.08). Mean total costs, comprising costs for study medications and their administration, inpatient care, transfusions, unplanned radiation therapy, haematology and laboratory services, chemotherapy and non-chemotherapy drugs and indirect costs were 14,976 US dollars in the epoetin alfa arm compared with 14,101 US dollars in the darbepoetin alfa arm, a difference of 875 US dollars (95% CI for difference -849, 2607), of which 98% of the difference was attributable to higher inpatient costs in the epoetin alfa arm (2374 US dollars vs 1520 US dollars; 95% CI for difference -33, 1955). Assessments of multiple clinical measures demonstrated improved outcomes with epoetin alfa relative to darbepoetin alfa. CONCLUSION: Most clinical outcome measures suggested greater improvement with epoetin alfa relative to darbepoetin alfa, but most costs for both agents appeared similar. Decision makers must evaluate the differences in costs and efficacy measures that are most relevant from their perspectives.     

Cost-minimization analysis of darbepoetin alfa versus epoetin alfa in the hospital setting.

PURPOSE: The cost of darbepoetin alfa versus that of epoetin alfa in a hospital setting was studied. METHODS: The study was an observational, retrospective review of the hospitalwide use of darbepoetin and epoetin during hospital admissions beginning in the period from January 2003 through April 2003. After the identification from daily charge reports of patients who used at least one of the study drugs during an admission, charts were requested for review. Drug product costs were determined from hospital purchasing information. Material and labor costs were combined to estimate drug administration costs. Total costs were calculated as the sum of drug product costs and administration costs. RESULTS: A total of 429 epoetin records and 80 darbepoetin records were included. The two cohorts were similar with respect to demographic characteristics. With respect to costs, the only significant difference between cohorts was in daily administration costs, which were lower for patients receiving darbepoetin. Sensitivity analysis found lower costs for darbepoetin only after the dose-conversion ratio (DCR) was increased to above 256.74 units:1 microg. The overall DCR based on the median daily dose of each drug was 244.90 units:1 microg. CONCLUSION: A cost-minimization study in a hospital showed no cost difference between treatment with epoetin and darbepoetin.     

Anemia treatment with Q2W darbepoetin alfa in patients with chronic kidney disease naïve to erythropoiesis-stimulating agents*

ABSTRACT

Objective: To evaluate the efficacy and safety of darbepoetin alfa dosed every-other-week (Q2W) to treat anemia in subjects with chronic kidney disease (CKD), not receiving dialysis, who were naïve to erythropoiesis-stimulating agent (ESA) therapy.

Research design and methods: This was an open-label, multicenter, single-arm study enrolling ESA-naïve CKD subjects with baseline hemoglobin (Hb)?<?11.0?g/dL. Q2W darbepoetin alfa treatment was initiated at a dose of 0.75?µg/kg and titrated to achieve and maintain Hb levels at 11.0–13.0?g/dL. Treatment was administered from week 1 to week 19.

Main outcome measures: The primary endpoint was the proportion of subjects who achieved Hb?≥?11?g/dL at any study visit, except in week 1. Hb levels, darbepoetin alfa dose, and safety were also assessed.

Results: Of the 128 subjects who received at least one dose of darbepoetin alfa and of the subjects who completed the study, 118 (92%) and 112 (97%), respectively, achieved a Hb?≥?11?g/dL in a median time of 5 weeks. Median darbepoetin alfa dose at week 1 and at the time of achieving a Hb?≥?11?g/dL were 60 and 80?µg, respectively. Darbepoetin alfa was well-tolerated, and short-term adverse events were consistent with those expected in CKD subjects.

Conclusions: This study demonstrates that de novo Q2W darbepoetin alfa was effective in correcting and maintaining Hb levels in ESA-naïve subjects with CKD who were not receiving dialysis. Study limitations, including lack of a control arm for the study and multiple race information for subjects, must be considered in interpreting the results.

Trial registration: ClinicalTrials.gov identifier: NCT00112008.     

Population pharmacokinetic model of fluvoxamine in rats: utility for application in animal behavioral studies.

The limitations of blood sampling in pharmacokinetic (PK)/pharmacodynamic (PD) studies in behavioral animal models could in part be overcome by a mixed effects modeling approach. This analysis characterizes and evaluates the population PK of fluvoxamine in rat plasma using nonlinear mixed effects modeling. The model is assessed for its utility in animal behavioral PK/PD studies. In six studies with a different experimental setup, study site and/or sampling design, rats received an intravenous infusion of 1, 3.7 or 7.3mg/kg fluvoxamine. A population three-compartment PK model adequately described the fluvoxamine plasma concentrations. Body weight was included as a covariate and mean population PK parameters for CL, V(1), V(2), Q(2), V(3) and Q(3) were 25.1 ml/min, 256 ml, 721 ml, 30.3 ml/min, 136 ml and 1.0 ml/min, respectively. Inter-individual variability was identified on CL (39.5%), V(1) (43.5%), V(2) (50.1%) and Q(2) (25.7%). A predictive check and bootstrap analysis confirmed the predictive ability, model stability and precision of the parameter estimates. Body weight was identified as a significant covariate of the inter-compartmental clearance Q(2). The pharmacokinetics was independent of factors such as dose, surgery (for instrumentation) and study site. The utility of the model in animal behavioral studies was demonstrated in a PK/PD analysis of the effects on REM sleep in which a sparse PK sampling design was used. By using the pertinent information from the population PK model, individual PK profiles and the PK/PD correlation could be adequately described.