title: 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.
  
  
  METHODS
  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).
  
  
  CONCLUSIONS
  Darbe combined with hypothermia has similar safety profile to placebo with pharmacokinetics sufficient for weekly administration.
authors.affiliation: Division of Neonatology, Department of Pediatrics, University of Utah, Salt Lake City, Utah.
authors.forename: Mariana C
authors.initials: MC
authors.lastname: Baserga
authors.affiliation: Division of Neonatology, Department of Pediatrics, University of Utah, Salt Lake City, Utah.
authors.forename: Joanna C
authors.initials: JC
authors.lastname: Beachy
authors.affiliation: Division of Clinical Pharmacology, Department of Pediatrics, University of Utah, Salt Lake City, Utah.
authors.forename: Jessica K
authors.initials: JK
authors.lastname: Roberts
authors.affiliation: 1] Division of Neonatology, Department of Pediatrics, University of Utah, Salt Lake City, Utah [2] Division of Clinical Pharmacology, Department of Pediatrics, University of Utah, Salt Lake City, Utah.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Ward
authors.affiliation: Division of Neonatology, Department of Pediatrics, University of Utah, Salt Lake City, Utah.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: DiGeronimo
authors.affiliation: Division of Neonatology, Department of Pediatrics, Vanderbilt University, Nashville, Tennessee.
authors.forename: William F
authors.initials: WF
authors.lastname: Walsh
authors.affiliation: Division of Neonatology, Department of Pediatrics, University of New Mexico, Albuquerque, New Mexico.
authors.forename: Robin K
authors.initials: RK
authors.lastname: Ohls
authors.affiliation: Division of Neonatology, Department of Pediatrics, University of New Mexico, Albuquerque, New Mexico.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Anderson
authors.affiliation: Division of Neonatology, Department of Pediatrics, University of Washington, Seattle, Washington.
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Mayock
authors.affiliation: Division of Neonatology, Department of Pediatrics, University of Washington, Seattle, Washington.
authors.forename: Sandra E
authors.identifier: 0000000268616229
authors.initials: SE
authors.lastname: Juul
authors.affiliation: Intermountain Healthcare, McKay Dee Hospital, Ogden, Utah.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Christensen
authors.affiliation: Division of Neonatology, Department of Pediatrics, University of Utah, Salt Lake City, Utah.
authors.forename: Manndi C
authors.initials: MC
authors.lastname: Loertscher
authors.affiliation: Division of Clinical Pharmacology, Department of Pediatrics, University of Utah, Salt Lake City, Utah.
authors.forename: Chris
authors.initials: C
authors.lastname: Stockmann
authors.affiliation: Division of Clinical Pharmacology, Department of Pediatrics, University of Utah, Salt Lake City, Utah.
authors.forename: Catherine M T
authors.initials: CM
authors.lastname: Sherwin
authors.affiliation: Division of Clinical Pharmacology, Department of Pediatrics, University of Utah, Salt Lake City, Utah.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Spigarelli
authors.affiliation: Division of Neonatology, Department of Pediatrics, University of Utah, Salt Lake City, Utah.
authors.forename: Bradley A
authors.initials: BA
authors.lastname: Yoder
mesh_terms: D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D001927:Brain Diseases / Q000188:drug therapy*; D000068256:Darbepoetin alfa / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004921:Erythropoietin / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007035:Hypothermia / Q000188:drug therapy; D007036:Hypothermia, Induced; D007231:Infant, Newborn; D008279:Magnetic Resonance Imaging; D008297:Male; D055815:Young Adult
chemical_list: D004921:Erythropoietin; D000068256:Darbepoetin alfa