title: Population Pharmacokinetics of Darbepoetin Alfa in Conjunction with Hypothermia for the Treatment of Neonatal Hypoxic-Ischemic Encephalopathy.
abstract: OBJECTIVE
  The aim of this study was to determine the population pharmacokinetics of darbepoetin alfa in hypothermic neonates with hypoxic-ischemic encephalopathy treated with hypothermia.
  
  
  METHODS
  Neonates ≥36 weeks gestation and <12 h postpartum with moderate to severe hypoxic-ischemic encephalopathy who were undergoing hypothermia treatment were recruited in this randomized, multicenter, investigational, new drug pharmacokinetic study. Two intravenous darbepoetin alfa treatment groups were evaluated: 2 and 10 µg/kg. Serum erythropoietin concentrations were measured using an enzyme-linked immunosorbent assay. Monolix 4.3.1 was used to estimate darbepoetin alfa clearance and volume of distribution. Covariates tested included: birthweight, gestational age, postnatal age, postmenstrual age, sex, Sarnat score, and study site.
  
  
  RESULTS
  Darbepoetin alfa pharmacokinetics were well described by a one-compartment model with exponential error. Clearance and the volume of distribution were scaled by birthweight (centered on the mean) a priori. Additionally, gestational age (also centered on the mean) significantly affected darbepoetin alfa clearance. Clearance and volume of distribution were estimated as 0.0465 L/h (95% confidence interval 0.0392-0.0537) and 1.58 L (95% confidence interval 1.29-1.87), respectively.
  
  
  CONCLUSIONS
  A one-compartment model successfully described the pharmacokinetics of darbepoetin alfa among hypothermic neonates treated for hypoxic-ischemic encephalopathy. Clearance decreased with increasing gestational age.
authors.affiliation: Division of Clinical Pharmacology, Department of Pediatrics, School of Medicine, University of Utah, 295 Chipeta Way, Salt Lake City, UT, 84108, USA.
authors.forename: Jessica K
authors.initials: JK
authors.lastname: Roberts
authors.affiliation: Division of Clinical Pharmacology, Department of Pediatrics, School of Medicine, University of Utah, 295 Chipeta Way, Salt Lake City, UT, 84108, USA.|Department of Pharmacology and Toxicology, College of Pharmacy, University of Utah, 295 Chipeta Way, Salt Lake City, UT, 84108, USA.
authors.forename: Chris
authors.initials: C
authors.lastname: Stockmann
authors.affiliation: Division of Clinical Pharmacology, Department of Pediatrics, School of Medicine, University of Utah, 295 Chipeta Way, Salt Lake City, UT, 84108, USA.|Department of Pharmacology and Toxicology, College of Pharmacy, University of Utah, 295 Chipeta Way, Salt Lake City, UT, 84108, USA.|Division of Neonatology, Department of Pediatrics, School of Medicine, University of Utah, 295 Chipeta Way, Salt Lake City, UT, 84108, USA.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Ward
authors.affiliation: Division of Neonatology, Department of Pediatrics, School of Medicine, University of Utah, 295 Chipeta Way, Salt Lake City, UT, 84108, USA.
authors.forename: Joanna
authors.initials: J
authors.lastname: Beachy
authors.affiliation: Division of Neonatology, Department of Pediatrics, School of Medicine, University of Utah, 295 Chipeta Way, Salt Lake City, UT, 84108, USA.
authors.forename: Mariana C
authors.initials: MC
authors.lastname: Baserga
authors.affiliation: Division of Clinical Pharmacology, Department of Pediatrics, School of Medicine, University of Utah, 295 Chipeta Way, Salt Lake City, UT, 84108, USA.|Department of Pharmacology and Toxicology, College of Pharmacy, University of Utah, 295 Chipeta Way, Salt Lake City, UT, 84108, USA.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Spigarelli
authors.affiliation: Division of Clinical Pharmacology, Department of Pediatrics, School of Medicine, University of Utah, 295 Chipeta Way, Salt Lake City, UT, 84108, USA. catherine.sherwin@hsc.utah.edu.
authors.forename: Catherine M T
authors.initials: CM
authors.lastname: Sherwin
mesh_terms: D061605:Administration, Intravenous; D000068256:Darbepoetin alfa / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D004311:Double-Blind Method; D004921:Erythropoietin / Q000097:blood; D005260:Female; D006397:Hematinics / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D006801:Humans; D007035:Hypothermia / Q000097:blood / Q000188:drug therapy / Q000378:metabolism / Q000628:therapy*; D007036:Hypothermia, Induced / Q000379:methods*; D020925:Hypoxia-Ischemia, Brain / Q000097:blood / Q000188:drug therapy / Q000378:metabolism / Q000628:therapy*; D007231:Infant, Newborn; D008297:Male
chemical_list: D006397:Hematinics; D004921:Erythropoietin; D000068256:Darbepoetin alfa