Darbepoetin administration to neonates undergoing cooling for encephalopathy: a safety and pharmacokinetic trial

Abstract

BACKGROUND Despite therapeutic hypothermia, neonates with encephalopathy (NE) have high rates of death or disability. Darbepoetin alfa (Darbe) has comparable biological activity to erythropoietin, but has extended circulating half-life (t1/2). Our aim was to determine Darbe safety and pharmacokinetics as adjunctive therapy to hypothermia. STUDY DESIGN Thirty infants (n = 10/arm) ≥36wk gestation undergoing therapeutic hypothermia for NE were randomized to receive placebo, Darbe low dose (2 μg/kg), or high dose (10 μg/kg) given intravenously within 12 h of birth (first dose/hypothermia condition) and at 7 d (second dose/normothermia condition). Adverse events were documented for 1 mo. Serum samples were obtained to characterize Darbe pharmacokinetics. RESULTS Adverse events (hypotension, altered liver and renal function, seizures, and death) were similar to placebo and historical controls. Following the first Darbe dose at 2 and 10 μg/kg, t1/2 was 24 and 32 h, and the area under the curve (AUCinf) was 26,555 and 180,886 h*mU/ml*, respectively. In addition, clearance was not significantly different between the doses (0.05 and 0.04 l/h). At 7 d, t1/2 was 26 and 35 h, and AUCinf was 10,790 and 56,233 h*mU/ml*, respectively (*P < 0.01). CONCLUSION Darbe combined with hypothermia has similar safety profile to placebo with pharmacokinetics sufficient for weekly administration.

High-Dose Erythropoietin and Hypothermia for Hypoxic-Ischemic Encephalopathy: A Phase II Trial

“…16,17 Darbepoetin, a long-acting formulation of Epo, has also been shown to be safe in newborns undergoing hypothermia for HIE. 58 Epo monotherapy, without hypothermia, may be useful for neonatal conditions other than HIE, such as perinatal stroke, 59 congenital heart disease, 60 and brain injury of prematurity. [61][62][63][64] This is the first clinical study of HIE that assesses biomarkers of efficacy to evaluate whether Epo provides additional neuroprotection to hypothermia.…”

Preschool Assessment of Preterm Infants Treated With Darbepoetin and Erythropoietin

“…Randomized studies of either erythropoietin 19,20 or darbepoetin 21 for treatment of hypoxic ischemic encephalopathy have reported pharmacokinetic evaluations that suggest neuroprotection, and safety profiles showed no adverse effects of either ESA in term infants. Doses in the DANCE (Darbepoetin Administration in Neonates undergoing Cooling for Encephalopathy) study were similar to the darbepoetin doses administered in our original randomized controlled trial, 8 although term infants only received 2 doses 1 week apart in the DANCE study, compared with up to 10 weekly doses in our study.…”

Darbepoetin Administration in Term and Preterm Neonates

“…Table 1 (13–17) presents AUC following administration of ESAs (Darbe or Epo) in animal models and neonates. Notably, it is clear that there have been limited studies evaluating Darbe dosing and pharmacokinetics in neonates.…”

“…Only one study to date has evaluated Darbe as a potential neuroprotective agent in term infants undergoing hypothermia as treatment for HIE. The DANCE study (Darbepoetin administered to neonates undergoing cooling for encephalopathy) lead by Baserga (17) enrolled 30 infants (≥36 weeks gestation) with moderate to severe HIE. Infants were randomized to placebo (n=10), 2 μg/kg Darbe (n=10) or 10 μg/kg Darbe (n=10) IV.…”

“…Serum samples were obtained at specific time points to determine pharmacokinetics. At 2 and 10 μg/kg Darbe, t 1/2 was 24 and 32 hours, and the area under the curve extrapolated to infinity (AUC inf ) was 26,555 (interquartile range (IRQ) 20,049–35,029) and 180,886 mU/mL (IRQ 146–568–199,680), respectively (17). The investigators concluded that the 10 μg/kg dose achieved an AUC in the neuroprotective range, and a terminal t 1/2 of 53.4 hours (5) when compared to the 2 μg/kg dose.…”