title: High-dose erythropoietin population pharmacokinetics in neonates with hypoxic-ischemic encephalopathy receiving hypothermia.
abstract: BACKGROUND
  High-dose erythropoietin (Epo) is a promising neuroprotective treatment in neonates with hypoxic-ischemic encephalopathy (HIE) receiving hypothermia. We evaluated the pharmacokinetics and dose-exposure relationships of high-dose Epo in this population to inform future dosing strategies.
  
  
  METHODS
  We performed a population pharmacokinetic analysis of 47 neonates with HIE treated with hypothermia who received up to six doses of Epo in two previous clinical trials. We compared the ability of different dosing regimens to achieve the target neuroprotective Epo exposure levels determined from animal models of hypoxic-ischemia (i.e., area under the curve during the first 48 h of treatment (AUC48 h) 140,000 mU*h/ml).
  
  
  RESULTS
  Birth weight scaled via allometry was a significant predictor of Epo clearance and volume of distribution (P < 0.001). After accounting for birth weight, variation in Epo pharmacokinetics between neonates was low (CV% 20%). All 23 neonates who received 1,000 U/kg every 24 h for the first 2 d of therapy achieved the target AUC48 h140,000 mU*h/ml. No neonate who received a lower dosing regimen achieved this target.
  
  
  CONCLUSIONS
  In neonates with HIE receiving hypothermia, Epo 1,000 U/kg every 24 h for the first 2 d of therapy resulted in consistent achievement of target exposures associated with neuroprotection in animal models.
authors.affiliation: Department of Pediatrics, Stanford University, Stanford, California.
authors.forename: Adam
authors.initials: A
authors.lastname: Frymoyer
authors.affiliation: Department of Pediatrics, University of Washington, Seattle, Washington.
authors.forename: Sandra E
authors.initials: SE
authors.lastname: Juul
authors.affiliation: Department of Neonatology, Children's National Health Systems, Washington, DC.
authors.forename: An N
authors.initials: AN
authors.lastname: Massaro
authors.affiliation: Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington.
authors.forename: Theo K
authors.initials: TK
authors.lastname: Bammler
authors.affiliation: Department of Neurology, University of California, San Francisco, California.|Department of Pediatrics, University of California, San Francisco, California.
authors.forename: Yvonne W
authors.initials: YW
authors.lastname: Wu
mesh_terms: D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D004921:Erythropoietin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D006801:Humans; D007036:Hypothermia, Induced; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy / Q000628:therapy*; D007231:Infant, Newborn
chemical_list: D004921:Erythropoietin