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Clinical Pharmacokinetics 2006The pharmacokinetics of darbepoetin alfa after intravenous (IV) administration in the oncology setting have not been previously reported. The objective of this study was...
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
darbepoetin alfa 2.25 microg/kg administered either IV (n=27) or SC (n=29) during up to three cycles of chemotherapy. Noncompartmental pharmacokinetic analysis was performed, including analysis of intensive pharmacokinetic profiles collected over 168 hours during week 1 of both the first and third cycles of chemotherapy. RESULTS
Darbepoetin alfa serum concentrations exhibited a biphasic profile (a rapid distributive phase followed by a slower terminal elimination phase) after IV administration, whereas darbepoetin alfa was slowly absorbed after SC administration. Darbepoetin alfa exhibited limited extravascular distribution after IV administration, with both initial and steady-state mean volumes of distribution (36.1 mL/kg and 55.2 mL/kg, respectively, after a single IV dose) approximating the plasma volume. After a single IV dose, darbepoetin alfa exhibited a mean clearance of 1.05 mL/h/kg, with a mean terminal half-life of 38.8 hours. Similar pharmacokinetic results were observed after single and multiple doses of darbepoetin alfa, for both SC and IV administration.
CONCLUSION
Darbepoetin alfa is cleared slowly after IV administration to patients with cancer receiving chemotherapy, resulting in a terminal half-life of 38.8 hours. No evidence of accumulation and no changes in pharmacokinetic profiles after repeated administration were observed in cancer patients undergoing cyclic chemotherapy, for both IV and SC dosing.
Topics: Absorption; Adult; Aged; Area Under Curve; Darbepoetin alfa; Erythropoietin; Female; Half-Life; Humans; Injections, Intravenous; Injections, Subcutaneous; Male; Metabolic Clearance Rate; Middle Aged; Neoplasms; Tissue Distribution
PubMed: 16485917
DOI: 10.2165/00003088-200645020-00005 -
Protein Expression and Purification Feb 2016Darbepoetin alfa is an engineered and hyperglycosylated analog of recombinant human erythropoietin (EPO) which is used as a drug in treating anemia in patients with...
Darbepoetin alfa is an engineered and hyperglycosylated analog of recombinant human erythropoietin (EPO) which is used as a drug in treating anemia in patients with chronic kidney failure and cancer. This study desribes the secretory expression of a codon-optimized recombinant form of darbepoetin alfa in Leishmania tarentolae T7-TR. Synthetic codon-optimized gene was amplified by PCR and cloned into the pLEXSY-I-blecherry3 vector. The resultant expression vector, pLEXSYDarbo, was purified, digested, and electroporated into the L. tarentolae. Expression of recombinant darbepoetin alfa was evaluated by ELISA, reverse-transcription PCR (RT-PCR), Western blotting, and biological activity. After codon optimization, codon adaptation index (CAI) of the gene raised from 0.50 to 0.99 and its GC% content changed from 56% to 58%. Expression analysis confirmed the presence of a protein band at 40 kDa. Furthermore, reticulocyte experiment results revealed that the activity of expressed darbepoetin alfa was similar to that of its equivalent expressed in Chinese hamster ovary (CHO) cells. These data suggested that the codon optimization and expression in L. tarentolae host provided an efficient approach for high level expression of darbepoetin alfa.
Topics: Animals; CHO Cells; Cloning, Molecular; Codon; Cricetinae; Cricetulus; Darbepoetin alfa; Gene Expression; Leishmania; Protein Engineering; Protozoan Proteins
PubMed: 26546410
DOI: 10.1016/j.pep.2015.10.013 -
American Journal of Nephrology 2006Hemodialysis patients are often hospitalized, during which time they require continuity of care in the inpatient setting. The goal of the present study was to evaluate...
BACKGROUND/AIMS
Hemodialysis patients are often hospitalized, during which time they require continuity of care in the inpatient setting. The goal of the present study was to evaluate the clinical outcomes associated with a conversion algorithm from outpatient epoetin alfa to inpatient darbepoetin alfa in hospitalized hemodialysis patients at the St. Elizabeth Health Center.
METHODS
We conducted a retrospective chart review of hemodialysis patient hospital admissions after a therapeutic interchange from epoetin alfa to darbepoetin alfa was implemented at St. Elizabeth Health Center. Chronic hemodialysis patients admitted from December 2002 to October 2003 were identified as part of a therapeutic interchange cohort receiving inpatient darbepoetin alfa after conversion from outpatient epoetin alfa according to the Aranesp package insert during their hospitalization. After discharge, these patients were returned to their preadmission outpatient epoetin alfa dosages and frequencies. Patients admitted prior to implementation of the therapeutic interchange (January 2002 to April 2002) received epoetin alfa during hospitalization and served as a historical control. Hemoglobin values were recorded prior to hospital admission, at the time of discharge, and 30 days after discharge.
RESULTS
Mean hemoglobin levels declined from preadmission to discharge, in both the interchange and historical cohorts (6.6 and 2.5%, respectively) and rebounded at 30 days after discharge. Using a linear regression model, the only variables significantly associated with the hemoglobin level at discharge were the hemoglobin level before admission and receipt of a blood transfusion.
CONCLUSION
An algorithm-based conversion from outpatient epoetin alfa to inpatient darbepoetin alfa for hospitalized chronic hemodialysis patients utilizing the dose conversion table specified in the Aranesp package insert is associated with hemoglobin outcomes similar to inpatient epoetin alfa.
Topics: Aged; Aged, 80 and over; Algorithms; Darbepoetin alfa; Epoetin Alfa; Erythropoietin; Female; Health Status; Hematinics; Hemoglobins; Hospitalization; Humans; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Retrospective Studies; Treatment Outcome
PubMed: 17170523
DOI: 10.1159/000098027 -
Nefrologia : Publicacion Oficial de La... Jan 2013The use of darbepoetin alfa in the first week of post-renal transplant (RT). (Observational Study)
Observational Study
BACKGROUND AND OBJECTIVES
The use of darbepoetin alfa in the first week of post-renal transplant (RT).
METHODS
Retrospective observational study carried out in four hospitals, which included all adult patients that underwent RT for 9 months with haemoglobin data during the first 6 months of post-transplant (n=129). Darbepoetin alfa was administered in accordance with the clinical practice.
RESULTS
Darbepoetin alfa was administered in the first week to 60 individuals (46.5%), who had a mean baseline Hb (± standard deviation) of 12.7 g/dl ± 1.6g/dl. Anaemia incidence (Hb<11 g/dl) during the first month was higher in patients who did not receive darbepoetin alfa (40.6% vs. 25.0% in patients treated with darbepoetin alfa, P=.045). No anaemia incidence differences were observed during months +2 to +6. There was a tendency towards transfusion decrease in patients who received darbepoetin alfa (13.3% vs. 20.3%, P=.295). Renal recovery time was similar but in the subgroup which received grafts from donors with asystole there was a tendency towards a faster recovery with darbepoetin alfa (15.1 ± 7.7 vs. 20.1 ± 8.8 days, P=.157). The creatinine clearance rate at 3 and 6 months was similar. Fourteen patients (10.9%) suffered from cardiovascular events with no relation to darbepoetin alfa (P=.772).
CONCLUSIONS
Administering darbepoetin alfa in the first week following renal transplant reduces anaemia incidence during the first month without increase cardiovascular events.
Topics: Anemia; Darbepoetin alfa; Erythropoietin; Female; Hematinics; Humans; Kidney Transplantation; Male; Middle Aged; Retrospective Studies
PubMed: 23364633
DOI: 10.3265/Nefrologia.pre2012.Oct.11473 -
BMC Cancer Oct 2010Chemotherapy-induced anemia (CIA) is responsive to treatment with erythropoiesis-stimulating agents (ESAs) such as darbepoetin alfa. Administration of ESAs on a... (Comparative Study)
Comparative Study Randomized Controlled Trial
Comparison of darbepoetin alfa dosed weekly (QW) vs. extended dosing schedule (EDS) in the treatment of anemia in patients receiving multicycle chemotherapy in a randomized, phase 2, open-label trial.
BACKGROUND
Chemotherapy-induced anemia (CIA) is responsive to treatment with erythropoiesis-stimulating agents (ESAs) such as darbepoetin alfa. Administration of ESAs on a synchronous schedule with chemotherapy administration could benefit patients by reducing clinic visits and potentially enhancing on-time chemotherapy delivery.
METHODS
This phase 2, 25-week, open-label study evaluated the noninferiority of darbepoetin alfa administered weekly vs. as an extended dosing schedule (every 2 or 3 weeks) in patients with CIA. Patients were randomized 1:1 to an extended dosing schedule (EDS: darbepoetin alfa 300 μg Q2W if chemotherapy was QW, Q2W, or Q4W or darbepoetin alfa 500 μg Q3W if chemotherapy was Q3W) or weekly (150 μg QW regardless of chemotherapy schedule). Stratification factors included chemotherapy cycle length, screening hemoglobin (<10 g/dL vs. ≥10 g/dL), and tumor type (lung/gynecological vs. other nonmyeloid malignancies). The primary endpoint was change in hemoglobin from baseline to Week 13.
RESULTS
Seven hundred fifty-two patients (374 QW patients; 378 EDS patients) received ≥1 dose of darbepoetin alfa and were included in the analysis. Demographics and disease state were similar between groups. Seventy-one percent of patients in the EDS group and 76% in the QW group achieved the target hemoglobin of ≥11.0 g/dL. There was a minimal difference in the primary endpoint of mean change in hemoglobin (baseline to Week 13) between the QW and the EDS groups (-0.04 g/dL; 95% confidence interval: -0.26, 0.17 g/dL). The upper limit of the 95% confidence interval was less than the prespecified limit of <0.75 g/dL, supporting noninferiority of the EDS dosing schedule. Reported adverse events were similar between groups. A slight increase in transfusions was reported in the QW group.
CONCLUSION
Darbepoetin alfa, when administered synchronously with chemotherapy, on an EDS appears to be similarly efficacious to darbepoetin alfa weekly dosing with no unexpected adverse events. This study provides prospective data on how multiple dosing regimens available with darbepoetin alfa can be synchronized with chemotherapy administered across a range of dosing schedules.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier NCT00144131.
Topics: Activities of Daily Living; Aged; Anemia; Antineoplastic Agents; Darbepoetin alfa; Drug Administration Schedule; Erythropoietin; Female; Hematinics; Humans; Male; Middle Aged; Neoplasms; Quality of Life; Time Factors; Treatment Outcome
PubMed: 20973982
DOI: 10.1186/1471-2407-10-581 -
American Journal of Kidney Diseases :... Jul 2002Darbepoetin alfa (Aranesp; Amgen, Thousand Oaks, CA) is a new erythropoiesis-stimulating protein with a threefold longer terminal half-life than recombinant human... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
BACKGROUND
Darbepoetin alfa (Aranesp; Amgen, Thousand Oaks, CA) is a new erythropoiesis-stimulating protein with a threefold longer terminal half-life than recombinant human erythropoietin (epoetin) in patients with chronic kidney disease (CKD). The purpose of this randomized, double-blind, noninferiority study is to determine whether darbepoetin alfa is as effective as epoetin for the treatment of anemia in hemodialysis patients when administered at a reduced dosing frequency.
METHODS
Patients receiving epoetin therapy were randomized to continue epoetin administered intravenously (IV) three times weekly (n = 338) or change to darbepoetin alfa administered IV once weekly (n = 169). The dose of darbepoetin alfa or epoetin was individually titrated to maintain hemoglobin concentrations within -1.0 to +1.5 g/dL (-10 to +15 g/L) of patients' baseline values and within a range of 9.0 to 13.0 g/dL (90 to 130 g/L) for up to 28 weeks (20-week dose-titration period followed by an 8-week evaluation period). The primary end point was change in hemoglobin level between baseline and the evaluation period (weeks 21 to 28).
RESULTS
Mean changes in hemoglobin levels from baseline to the evaluation period were 0.24 +/- 0.10 (SE) g/dL (2.4 +/- 1.0 g/L) in the darbepoetin alfa group and 0.11 +/- 0.07 g/dL (1.1 +/- 0.7 g/L) in the epoetin group, a difference of 0.13 g/dL (95% confidence interval [CI], -0.08 +/- 0.33 [1.3 g/L; 95% CI, -0.8 to 3.3]). This difference was not statistically significant or clinically relevant despite the reduced frequency of darbepoetin alfa administration. The safety profile of darbepoetin alfa was similar to that of epoetin, and no antibody formation to either treatment was detected.
CONCLUSION
These results show that darbepoetin alfa maintains hemoglobin concentrations as effectively and safely as epoetin in patients with CKD, but with a reduced dosing frequency.
Topics: Adult; Aged; Aged, 80 and over; Anemia; Canada; Darbepoetin alfa; Double-Blind Method; Drug Administration Schedule; Epoetin Alfa; Erythropoiesis; Erythropoietin; Female; Humans; Injections, Intravenous; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Treatment Outcome; United States
PubMed: 12087568
DOI: 10.1053/ajkd.2002.33919 -
Leukemia & Lymphoma Jun 2010To evaluate efficacy, safety, changes in biological features, and quality of life (QoL) in low-risk anemic patients with MDS treated with darbepoetin alfa (DPO), 41...
To evaluate efficacy, safety, changes in biological features, and quality of life (QoL) in low-risk anemic patients with MDS treated with darbepoetin alfa (DPO), 41 patients received DPO 150 microg weekly for 24 weeks. The dose was increased to 300 microg weekly in non-responsive patients. During treatment, 10/17 (59%) transfusion-dependent (TD) and 13/23 (56%) transfusion-free (TF) patients responded. In TF patients, Hb increased from 9.2 +/- 0.9 g/dL to 10.3 +/- 1.4 g/dL by 24 weeks (p = 0.004). The mean response duration was 22 weeks (95% CI: 19.7-24.0) in TF patients compared with 15.1 weeks (95% CI: 13.3-17.5) in TD patients. Response to treatment was associated with increases in QoL. Decreases in the percentage of apoptotic progenitor cells (p = 0.007) and CD34+ cells (p = 0.005) were observed. These results confirm previous studies demonstrating the safety and efficacy of DPO in anemic patients with MDS. Biological changes and improvement in QoL were associated with response. Adequate dosing is to be determined.
Topics: Aged; Aged, 80 and over; Anemia; Blood Transfusion; Combined Modality Therapy; Darbepoetin alfa; Dose-Response Relationship, Drug; Erythropoietin; Female; Hematinics; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Proportional Hazards Models; Prospective Studies; Quality of Life; Regression Analysis; Treatment Outcome
PubMed: 20367566
DOI: 10.3109/10428191003728610 -
The Journal of Supportive Oncology 2005
Topics: Age Factors; Aged; Anemia; Clinical Trials as Topic; Darbepoetin alfa; Dose-Response Relationship, Drug; Erythropoietin; Humans; Neoplasms; Treatment Outcome
PubMed: 15794499
DOI: No ID Found -
Therapeutic Apheresis and Dialysis :... Apr 2020The objective of this study was to evaluate the safety and efficacy of JR-131, a biosimilar of darbepoetin alfa, for long-term treatment of renal anemia patients... (Comparative Study)
Comparative Study
The objective of this study was to evaluate the safety and efficacy of JR-131, a biosimilar of darbepoetin alfa, for long-term treatment of renal anemia patients undergoing hemodialysis. In this multicenter, single-arm, phase 3 study, 159 patients with renal anemia who had been receiving darbepoetin alfa or recombinant human erythropoietins were treated with intravenous JR-131 for 52 weeks. In patients receiving darbepoetin alfa, JR-131 was administered at the same dose, while in patients receiving recombinant human erythropoietin the dose was determined based on the 1:200 conversion ratio following the Japanese darbepoetin alfa package insert. No notable adverse drug reactions were reported, and no anti-JR-131 antibodies were detected. The hemoglobin levels were maintained in the range of 10.0-12.0 g/dL throughout the study. JR-131 proved to be a useful and lower-cost alternative to darbepoetin alfa in the management of renal anemia in patients undergoing hemodialysis.
Topics: Adult; Aged; Aged, 80 and over; Anemia; Biosimilar Pharmaceuticals; Darbepoetin alfa; Female; Hematinics; Hemoglobins; Humans; Japan; Male; Middle Aged; Prospective Studies; Renal Dialysis; Renal Insufficiency, Chronic; Time Factors
PubMed: 31304637
DOI: 10.1111/1744-9987.13420 -
Clinical and Experimental Nephrology Aug 2013Darbepoetin alfa (DA) is an attractive alternative to recombinant human erythropoietin (rHuEPO) in managing renal anemia. Since DA has not been approved by the... (Clinical Trial)
Clinical Trial
BACKGROUND
Darbepoetin alfa (DA) is an attractive alternative to recombinant human erythropoietin (rHuEPO) in managing renal anemia. Since DA has not been approved by the appropriate Japanese drug regulatory agencies for the indication of renal anemia in children in Japan, we have conducted a multicenter prospective study to determine the efficacy and safety of DA in Japanese children undergoing peritoneal dialysis (PD).
METHODS
Pediatric patients subcutaneously receiving rHuEPO were switched to DA treatment for a period of 28 weeks. The conversion to the initial dose of DA was calculated as 1 μg DA for 200 IU rHuEPO, and DA was administered intravenously once every 2 weeks. The target hemoglobin (Hb) concentration was defined as 11.0 to ≤13.0 g/dL. In some patients, the dose of DA was adjusted appropriately to achieve this target level, and/or the dosing frequency changed to once every 4 weeks.
RESULTS
In the 25 patients switched from rHuEPO to DA the mean Hb concentration increased from 9.9 ± 1.0 to 11.1 ± 1.0 g/dL at 8 weeks following commencement of the DA treatment. The target Hb concentration was achieved in 88 % of these patients, and 60 % maintained this target value on completion of the study. The dosing frequency was extended to once every 4 weeks in 60 % of patients. Twenty-four adverse events were noted in 11 of 25 patients (44 %); however, there was no causality between DA and adverse events.
CONCLUSIONS
The results of this study suggest that intravenous administration of DA once every 2 or 4 weeks is an effective and safe treatment for renal anemia in Japanese children undergoing PD.
Topics: Adolescent; Anemia; Child; Child, Preschool; Darbepoetin alfa; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Male; Peritoneal Dialysis; Prospective Studies
PubMed: 23089940
DOI: 10.1007/s10157-012-0714-3