title: Erythropoietin for neuroprotection in neonatal encephalopathy: safety and pharmacokinetics.
abstract: OBJECTIVE
  To determine the safety and pharmacokinetics of erythropoietin (Epo) given in conjunction with hypothermia for hypoxic-ischemic encephalopathy (HIE). We hypothesized that high dose Epo would produce plasma concentrations that are neuroprotective in animal studies (ie, maximum concentration = 6000-10000 U/L; area under the curve = 117000-140000 U*h/L).
  
  
  METHODS
  In this multicenter, open-label, dose-escalation, phase I study, we enrolled 24 newborns undergoing hypothermia for HIE. All patients had decreased consciousness and acidosis (pH < 7.00 or base deficit ≥ 12), 10-minute Apgar score ≤ 5, or ongoing resuscitation at 10 minutes. Patients received 1 of 4 Epo doses intravenously: 250 (N = 3), 500 (N = 6), 1000 (N = 7), or 2500 U/kg per dose (N = 8). We gave up to 6 doses every 48 hours starting at <24 hours of age and performed pharmacokinetic and safety analyses.
  
  
  RESULTS
  Patients received mean 4.8 ± 1.2 Epo doses. Although Epo followed nonlinear pharmacokinetics, excessive accumulation did not occur during multiple dosing. At 500, 1000, and 2500 U/kg Epo, half-life was 7.2, 15.0, and 18.7 hours; maximum concentration was 7046, 13780, and 33316 U/L, and total Epo exposure (area under the curve) was 50306, 131054, and 328002 U*h/L, respectively. Drug clearance at a given dose was slower than reported in uncooled preterm infants. No deaths or serious adverse effects were seen.
  
  
  CONCLUSIONS
  Epo 1000 U/kg per dose intravenously given in conjunction with hypothermia is well tolerated and produces plasma concentrations that are neuroprotective in animals. A large efficacy trial is needed to determine whether Epo add-on therapy further improves outcome in infants undergoing hypothermia for HIE.
authors.affiliation: Departments of Neurology, University of California, San Francisco, Child Neurology, 350 Parnassus Ave, Suite 609, San Francisco, CA 94143-0137, USA. wuy@neuropeds.ucsf.edu
authors.forename: Yvonne W
authors.initials: YW
authors.lastname: Wu
authors.forename: Larry A
authors.initials: LA
authors.lastname: Bauer
authors.forename: Roberta A
authors.initials: RA
authors.lastname: Ballard
authors.forename: Donna M
authors.initials: DM
authors.lastname: Ferriero
authors.forename: David V
authors.initials: DV
authors.lastname: Glidden
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Mayock
authors.forename: Taeun
authors.initials: T
authors.lastname: Chang
authors.forename: David J
authors.initials: DJ
authors.lastname: Durand
authors.forename: Dongli
authors.initials: D
authors.lastname: Song
authors.forename: Sonia L
authors.initials: SL
authors.lastname: Bonifacio
authors.forename: Fernando F
authors.initials: FF
authors.lastname: Gonzalez
authors.forename: Hannah C
authors.initials: HC
authors.lastname: Glass
authors.forename: Sandra E
authors.initials: SE
authors.lastname: Juul
mesh_terms: D000704:Analysis of Variance; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004921:Erythropoietin / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D005260:Female; D006207:Half-Life; D006801:Humans; D007036:Hypothermia, Induced; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy* / Q000628:therapy; D007231:Infant, Newborn; D007262:Infusions, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate; D018696:Neuroprotective Agents / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use
chemical_list: D018696:Neuroprotective Agents; D004921:Erythropoietin