Darbepoetin alfa has a longer circulating half-life and greater in vivo potency than recombinant human erythropoietin

Egrie, Joan C.; Dwyer, Erik; Browne, Jeffrey K.; Hitz, A.; Lykos, Michele A

doi:10.1016/s0301-472x(03)00006-7

Cited by 390 publications

(260 citation statements)

References 39 publications

Supporting

Mentioning

249

Contrasting

Unclassified

Order By: Relevance

“…Therefore, there may be an optimal range of association of these parameters where the balance between receptor affinity, half-life, dose, and dosing interval is a beneficial one. In comparison with rHuEPO, darbepoetin alfa had a threefold longer serum half-life in animals [47] and humans [48][49][50]. In patients on peritoneal dialysis, the terminal half-life of darbepoetin alfa after intravenous administration in patients was approximately 25 h, and following subcutaneous administration, the half-life was approximately 49 h [50,51] (Fig.…”

Section: Successful Development Of Darbepoetin Alfamentioning

confidence: 99%

Discovery and basic pharmacology of erythropoiesis-stimulating agents (ESAs), including the hyperglycosylated ESA, darbepoetin alfa: an update of the rationale and clinical impact

Kiss¹,

Elliott

Jedynasty³

et al. 2010

Eur J Clin Pharmacol

View full text Add to dashboard Cite

Cloning of the human erythropoietin (EPO) gene and development of the first recombinant human erythropoietin (rHuEPO) drug were truly breakthroughs. This allowed a deeper understanding of the structure and pharmacology of rHuEpo, which in turn inspired the discovery and development of additional erythropoiesisstimulating agents (ESAs). In vivo specific activity and serum half-life of rHuEPO are influenced by the amount and structure of the attached carbohydrate. Increased numbers of sialic acids on carbohydrate attached to rHuEPO correlated with a relative increase in in-vivospecific activity and increased serum half-life. The effect of increasing the number of sialic-acid-containing carbohydrates on in-vivo-specific activity was explored. Initial research focused on solving the problem of how the protein backbone could be engineered so a cell would add more carbohydrate to it. Additional work resulted in darbepoetin alfa, a longer-acting molecule with two additional carbohydrate chains.

show abstract

Section: Successful Development Of Darbepoetin Alfamentioning

confidence: 99%

Discovery and basic pharmacology of erythropoiesis-stimulating agents (ESAs), including the hyperglycosylated ESA, darbepoetin alfa: an update of the rationale and clinical impact

Kiss¹,

Elliott

Jedynasty³

et al. 2010

Eur J Clin Pharmacol

View full text Add to dashboard Cite

show abstract

“…Conventional r-HuEPO requires two to three subcutaneous or intravenous injections per week over long periods of time, until successful kidney transplantation restores kidney function. By contrast, darbepoetin alpha (DA) that has an increased sialic acid carbohydrate content promotes decreased clearance and has a longer serum halflife than r-HuEPO [12][13][14], allowing a single weekly administration. Previous studies showed a similar potent effect of darbepoetin in adult as well as in paediatric patients either in pre-dialysis chronic renal failure or in end stage renal failure [8,[14][15][16][17][18][19].…”

Section: Introductionmentioning

confidence: 99%

Darbepoetin, effective treatment of anaemia in paediatric patients with chronic renal failure

et al. 2007

View full text Add to dashboard Cite

Darbepoetin alfa (DA) is a unique long-acting treatment for anaemia in patients with chronic renal failure (CRF). This study assessed the mean dose of DA to achieve and maintain haemoglobin (Hb) levels between 11 g/dl and 13 g/dl in CRF children aged 11 years to 18 years. This observational, prospective study was conducted in 39 patients treated with DA. Twenty-nine patients were switched from recombinant human erythropoietin (r-HuEPO), and ten patients were naive to r-HuEPO. Naive patients received initial doses of 0.45 μg/kg of DA. Switched patients received a dose adjusted to the prior dose of r-HuEPO (200 IU r-HuEPO:1 μg DA). Among the switched patients, 79.3% received dialysis. No naive patients underwent dialysis. Overall, 74% of patients showed increased Hb level, with a mean value of 11.6±1.6 g/dl, using a mean DA dose of 0.63±0.48 μg/kg per week, and 66.7% patients reached the Pediatr Nephrol (2007) target Hb level. Hb increased in naive patients from 9.5 (95% CI: 7.7, 11.4) to 11.7 (95% CI: 10.9, 12.6) g/dl and in switched patients from 11.1 (95% CI: 10.6, 11.5) to 11.5 (95% CI: 10.8, 12.2) g/dl). Higher doses of DA were needed in the "switched" than in the "naive" patients to maintain Hb levels over 11 g/dl, respectively 0.73 (95% CI: 0.54, 0.92) and 0.34 (95% CI: 0.16, 0.52) μg/kg per week. Our results indicate the doses of DA necessary to treat CRF patients aged 11 years to 18 years. DA was an effective treatment to stabilise CRF patients at extended dosing intervals.

show abstract

“…This model enabled the testing of novel strategies such as infrequent dosing and once-per-cycle dosing with darbepoetin alpha, the erythropoiesis-stimulating protein, that has an extended half-life and increased in vivo biological activity compared with recombinant human erythropoietin (rHu-EPO; Egrie et al, 2003;Elliott et al, 2003). We examined whether darbepoetin alpha could 'sensitize' erythropoiesis to chemotherapy and lead to a worsening of postchemotherapy anaemia.…”

mentioning

confidence: 99%

Kinetics of haematopoietic recovery after dose‐intensive chemo/radiotherapy in mice: optimized erythroid support with darbepoetin alpha

et al. 2003

View full text Add to dashboard Cite

Summary. Despite its frequency and impact on clinical outcomes, anaemia in cancer patients remains poorly understood and suboptimally treated. The definition of optimum treatment schedules with erythropoietic agents requires a suitable model of chemotherapy-induced progressive anaemia. This study investigated novel strategies such as once-per-chemotherapy-cycle dosing, synchronization between erythroid supportive care and chemotherapy, and definition of the optimum timing of erythroid support. A murine model of carboplatin chemotherapy/radiotherapy (CRT)-induced anaemia was used, which caused progressive anaemia across multiple cycles. Weekly administration of recombinant human erythropoietin (rHuEPO) was effective, but the longer-acting darbepoetin alpha resulted in superior responses. In all animals, anaemia became progressive and more refractory across cycles because of accumulated bone marrow damage. Exploiting a specific enzyme-linked immunosorbent assay, which could distinguish between darbepoetin alpha and endogenous erythropoietin, the effect of CRT upon the pharmacokinetics of darbepoetin alpha showed that clearance of darbepoetin alpha, and presumably erythropoietin, was at least partially dependent on a chemotherapy-sensitive pathway. Scheduling data suggested that administration of erythropoietic agents prior to chemotherapy was more effective than administration after chemotherapy. There was no evidence that erythropoietic agents exacerbated anaemia, even when administered immediately prior to CRT in an attempt to 'prime' erythroid cells for the effects of CRT.

show abstract

Darbepoetin alfa has a longer circulating half-life and greater in vivo potency than recombinant human erythropoietin

Cited by 390 publications

References 39 publications

Discovery and basic pharmacology of erythropoiesis-stimulating agents (ESAs), including the hyperglycosylated ESA, darbepoetin alfa: an update of the rationale and clinical impact

Discovery and basic pharmacology of erythropoiesis-stimulating agents (ESAs), including the hyperglycosylated ESA, darbepoetin alfa: an update of the rationale and clinical impact

Darbepoetin, effective treatment of anaemia in paediatric patients with chronic renal failure

Kinetics of haematopoietic recovery after dose‐intensive chemo/radiotherapy in mice: optimized erythroid support with darbepoetin alpha

Contact Info

Product

Resources

About