A single s.c. dose of darbepoetin given to preterm neonates accelerated effective erythropoiesis. The pharmacodynamic and pharmacokinetic findings suggest that darbepoetin dosing in neonates would require a higher unit dose/kg and a shorter dosing interval than are generally used for anemic adults.
Objective: Feeding intolerance is a common problem in the neonatal intensive care unit (NICU) and some cases might be causally related to atrophic changes in the small bowel mucosa. We speculated that for such patients, feeding tolerance might improve after oral administration of enterocyte growth factors in a sterile, isotonic solution patterned after amniotic fluid.Study Design: Twenty neonates meeting criteria for feeding intolerance were eligible for this trial. They were randomized to either Group 1 (test solution) or Group 2 (control). Group 1 received 2.5 ml of test solution/kg every 3 h by oral-gastric or nasal-gastric (OG/NG) tube. This was begun when the patient was NPO because of feeding intolerance and continued until 80 ml/k/day of milk feedings were tolerated, or for a maximum of 7 days. Group 2 received a sham OG/NG administration every 3 h, until 80 ml/k/day of milk feedings were tolerated, or for a maximum of 7 days. Only the bedside nurse and the NICU pharmacist were aware which patients received the test solution and which received the sham administrations. The volumes of milk feedings were increased by order of the attending neonatologist and nurse practitioner. The study outcome was enteral calories/kg/day during and for 7 days after the cessation of the treatments.Results: Eleven patients were randomized to receive the test solution and nine to receive sham administrations. At study entry, the two groups were not different in gestational age, postnatal age, signs of feeding intolerance or cal/k/day taken enterally during the previous 3 days. The study doses were given for an average of just under 6 days (range, 2 to 7 days). During the week following the administrations, the test solution recipients trended toward more enteral calories. Specifically, they had an increase averaging 78±20.8 cal/k/day more than before the study, whereas the sham recipients had an increase averaging 55.9±33 cal/k/day more than before the study (P ¼ 0.05 for a one-sided test and P ¼ 0.10 for a two-sided test). The test solution recipients also had a trend toward fewer formula changes than did the sham recipients (P ¼ 0.10). Conclusion:In this small, randomized, controlled, masked trial, the administration of a sterile, non-caloric, growth factor containing solution patterned after human amniotic fluid was associated with trends that we interpret as reflecting better tolerance of milk feedings. On this basis, we suggest that a phase III efficacy trial should be accomplished, using the present data for sample size calculations.
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.
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