Darbepoetin Administration to Neonates Undergoing Cooling for Encephalopathy: A Safety and Pharmacokinetic Trial

Document Type

Article

Publication Date

5-2015

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) ≥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, 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.

DOI

10.1038/pr.2015.101

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