Darbepoetin Administration to Neonates Undergoing Cooling for Encephalopathy (DANCE): A Safety and Pharmacokinetic Trial.
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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.Thirty infants (n=10/arm) ≥36 weeks 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 hours of birth (1(st) dose/hypothermia condition) and at 7 days (2(nd) dose/normothermia condition). Adverse events were documented for 1 month. Serum samples were obtained to characterize Darbe pharmacokinetics.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 hours, 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 L/h and 0.04 L/h). At 7 days, t1/2 was 26 and 35 hours, and AUCinf was 10,790 and 56,233 h*mU/mL*, respectively (*P<0.01).Darbe combined with hypothermia has similar safety profile to placebo with pharmacokinetics sufficient for weekly administration.Pediatric Research (2015); doi:10.1038/pr.2015.101.