Intravenous administration of darbepoetin to NICU patients

Abstract

Objective: Darbepoetin can be administered either intravenously (i.v.) or subcutaneously (s.c.). However, no information is available regarding pharmacokinetics and pharmacodynamics following its i.v. administration to neonates. Study design:We administered a single i.v. dose (4 mg/kg) of darbepoetin to 10 neonates who had a hemoglobin p10.5 g/dl. Blood was obtained for immature reticulocyte fraction (IRF) and absolute reticulocyte count (ARC), before and 48 h following the dose. Blood was also drawn for pharmacokinetic analysis once before and at four pre-set intervals after dosing. Results:The study subjects ranged from 704 to 3025 g (median, 1128 g) birth weight, and were 26.0-40.0 weeks (median, 29.2 weeks) gestation at delivery. When the darbepoetin dose was given, ages ranged from 3 to 28 days (median, 8.5 days) with a hemoglobin of 9.8±0.7 g/dl (mean±s.d.). Doses were administered by i.v. infusion over 4 h. No adverse effects of the infusions were detected. The half-life of darbepoetin (t 1/2 ) was 10.1 h (range 9.0-22.7 h), the volume of distribution was 0.77 l/kg (range 0.18-3.05 l/kg) and the clearance was 52.8 ml/h/kg (range 22.4-158.0 ml/h/kg). In the preterm neonates, there was no significant correlation between gestational age, or age at darbepoetin administration, and pharmacokinetic parameters. However, in the term and near-term neonates, volume of distribution correlated significantly with both gestational and age at darbepoetin administration (P<0.05). Forty-eight hours after dosing, the IRFs and ARCs were elevated in six subjects and not in four. Those with predosing reticulocyte counts >200 000/ml did not have an increase in reticulocytes by 48 h (P<0.05).Conclusions: Darbepoetin administered i.v. to neonates had a shorter t 1/ 2 , a larger volume of distribution and more rapid clearance than reported in children. We observed a significantly shorter t 1/2 and a less consistent rise in IRF and ARC after i.v. dosing than we previously reported following 4 mg/kg administered SC. Journal of Perinatology (2006) IntroductionThe darbepoetin molecule was created by biologically modifying recombinant erythropoietin (rEpo) in order to generate five carbohydrate-binding sites, compared with three in rEpo. This modification produced a more potent erythropoietic stimulator with the advantage of requiring less frequent dosing.

Cognitive Outcomes of Preterm Infants Randomized to Darbepoetin, Erythropoietin, or Placebo

“…Evaluation of single-dose pharmacokinetics in preterm infants revealed a similar prolonged half-life. 3,4 Recent studies in animals and humans evaluating the non-hematopoietic effects of ESAs suggest a strong potential for neuroprotection via a variety of mechanisms, including oligodendrogenesis, decreased inflammation, decreased oxidative injury,anddecreasedapoptosis. [5][6][7][8][9] Our group previously reported an increased mental developmental index in former extremely low birth weight (ELBW) infants who had serum Epo concentrations .500 mU/mL, 10 and Neubauer et al reported improved developmental outcomes at 8 to 12 years in former Epotreated preterm infants.…”

“…Importantly, Darbe provided this effect with weekly dosing. Given its significantly longer half-life, 3,4 Darbe may be the more attractive and practical choice of ESA for preterm infants. There were no differences in hearing or visual impairment, but significant differences in the incidence of CP were noted, in that only infants in the placebo group had CP identified by examiners masked to the treatment group.…”

Urinary excretion of darbepoetin after intravenous vs subcutaneous administration to preterm neonates

“…We used a darbepoetin dose of 4 mg/kg on the basis of our previous pharmacokinetic studies. 3,4 This dose is a much higher unit dose than that given by Buhrer and Obladen. If the conversion factor of 1 mg darbepoetin ¼ 400 U rEpo is used, 4,5 our dose was 6.4 times higher than the Buhrer and Obladen dose.…”

“…or subcutaneous (s.c.) route of administration. 3,4 Our recent studies, and unpublished data cited by the manufacturer, 5 suggest that s.c. dosing may be more effective in stimulating erythropoiesis than i.v. dosing, but this has not been tested directly.…”

Very low birth weight infants qualifying for a ‘late’ erythrocyte transfusion: Does giving darbepoetin along with the transfusion counteract the transfusion's erythropoietic suppression?

“…13,14 On the basis of our pharmacokinetic studies of darbepoetin administration to VLBW neonates, [15][16][17] we hypothesized that when a neonate qualifies for a late RBC transfusion, a single dose of darbepoetin would counteract the transfusion's erythrosuppressive effect. The single-dose concept was derived from our studies, [15][16][17] and that of Freise et al, 18 who calculated that among VLBW neonates, only a modest increase in plasma erythropoietin is needed to effectuate a several-fold increase in erythropoiesis. With this information, we reasoned that the strategy of single-dose darbepoetin administration accompanying a late transfusion might be worth testing as a means of preventing further NICU transfusions.…”