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 (t 1/2). Our aim was to determine Darbe safety and pharmacokinetics as adjunctive therapy to hypothermia.Study design:Thirty infants (n = 10/arm) ≥36 wk 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, t 1/2 was 24 and 32 h, and the area under the curve (AUC inf) 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, t 1/2 was 26 and 35 h, and AUC inf 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.