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.

• Authors: Mariana C Baserga, Joanna C Beachy, Jessica K Roberts, Robert M Ward, Robert J DiGeronimo, William F Walsh, Robin K Ohls, Jennifer Anderson, Dennis E Mayock, Sandra E Juul, Robert D Christensen, Manndi C Loertscher, Chris Stockmann, Catherine M T Sherwin, Michael G Spigarelli, Bradley A Yoder
• Journal: Pediatric research (Pediatr Res) Vol. 78 Issue 3 Pg. 315-22 (Sep 2015) ISSN: 1530-0447 [Electronic] United States
• PMID: 25996892 (Publication Type: Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Erythropoietin
• Darbepoetin alfa

Topics

• Adolescent
• Adult
• Area Under Curve
• Brain Diseases (drug therapy)
• Darbepoetin alfa (pharmacokinetics, therapeutic use)
• Dose-Response Relationship, Drug
• Drug Administration Schedule
• Erythropoietin (therapeutic use)
• Female
• Humans
• Hypothermia (drug therapy)
• Hypothermia, Induced
• Infant, Newborn
• Magnetic Resonance Imaging
• Male
• Young Adult