title: A phase I/II trial of high-dose erythropoietin in extremely low birth weight infants: pharmacokinetics and safety.
abstract: OBJECTIVE
  High-dose recombinant erythropoietin is neuroprotective in animal models of neonatal brain injury. Extremely low birth weight infants are at high risk for brain injury and neurodevelopmental problems and might benefit from recombinant erythropoietin. We designed a phase I/II trial to test the safety and determine the pharmacokinetics of high-dose recombinant erythropoietin in extremely low birth weight infants.
  
  
  METHODS
  In a prospective, dose-escalation, open-label trial, we compared 30 infants who were treated with high-dose recombinant erythropoietin with 30 concurrent control subjects. Eligible infants were <24 hours old, <or=1000 g birth weight, and <or=28 weeks of gestation and had an umbilical artery catheter in place. Each infant received 3 intravenous doses of 500, 1000, or 2500 U/kg at 24-hour intervals beginning on day 1 of age. Blood samples were collected at scheduled intervals to determine recombinant erythropoietin pharmacokinetics. Safety parameters were also evaluated. In the concurrent control group, only clinical data were collected.
  
  
  RESULTS
  Mean erythropoietin concentrations 30 minutes after recombinant erythropoietin infusion were 5973 +/- 266, 12291 +/- 403, and 34197 +/- 1641 mU/mL after 500, 1000, or 2500 U/kg, respectively. High-dose recombinant erythropoietin followed nonlinear pharmacokinetics as a result of decreasing clearance from the lowest dosage (17.3 mL/hour per kg for 500 U/kg) to the highest dosage (8.2 mL/hour per kg for 2500 U/kg). Steady state was achieved within 24 to 48 hours. Both 1000 and 2500 U/kg recombinant erythropoietin produced peak serum erythropoietin concentrations that were comparable to neuroprotective concentrations that previously were seen in experimental animals. No excess adverse events occurred in the recombinant erythropoietin-treated infants compared with control infants.
  
  
  CONCLUSIONS
  Early high-dose recombinant erythropoietin is well tolerated by extremely low birth weight infants, causing no excess morbidity or mortality. Recombinant erythropoietin dosages of 1000 and 2500 U/kg achieved neuroprotective serum levels.
authors.affiliation: Department of Pediatrics, University of Washington, Seattle, Washington 98195, USA. sjuul@u.washington.edu
authors.forename: Sandra E
authors.initials: SE
authors.lastname: Juul
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: McPherson
authors.forename: Larry A
authors.initials: LA
authors.lastname: Bauer
authors.forename: Kelly J
authors.initials: KJ
authors.lastname: Ledbetter
authors.forename: Christine A
authors.initials: CA
authors.lastname: Gleason
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Mayock
mesh_terms: D000704:Analysis of Variance; D001927:Brain Diseases / Q000188:drug therapy / Q000401:mortality / Q000517:prevention & control*; D002658:Developmental Disabilities / Q000188:drug therapy* / Q000401:mortality / Q000517:prevention & control; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004921:Erythropoietin / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D005260:Female; D005500:Follow-Up Studies; D005865:Gestational Age; D006801:Humans; D052577:Infant, Extremely Low Birth Weight; D007231:Infant, Newborn; D007235:Infant, Premature, Diseases / Q000188:drug therapy* / Q000401:mortality / Q000517:prevention & control; D007262:Infusions, Intravenous; D008297:Male; D011446:Prospective Studies; D011994:Recombinant Proteins; D012016:Reference Values; D018570:Risk Assessment; D016037:Single-Blind Method; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D011994:Recombinant Proteins; D004921:Erythropoietin