title: Development and verification of a pharmacokinetic model to optimize physiologic replacement of rhIGF-1/rhIGFBP-3 in preterm infants.
abstract: rhIGF-1/rhIGFBP-3 is being investigated for prevention of retinopathy of prematurity in extremely preterm infants.
  
  
  
  A population pharmacokinetic model was developed using data from phase I/II (Sections A-C) trials of rhIGF-1/rhIGFBP-3 and additional studies in preterm infants to predict optimal dosing to establish/maintain serum IGF-1 within physiological intrauterine levels. In Section D of the phase II study, infants (gestational age (GA) (wk+d) 23+0 to 27+6) were randomized to rhIGF-1/rhIGFBP-3, administered at the model-predicted dose of 250 µg/kg/d continuous i.v. infusion up to postmenstrual age (PMA) 29 wk+6 d or standard of care. An interim pharmacokinetic analysis was performed for the first 10 treated infants to verify dosing.
  
  
  
  Serum IGF-1 data were reviewed for 10 treated/9 control infants. Duration of therapy in treated infants ranged 1-34.5 d. At baseline (before infusion and <24 h from birth), mean (SD) IGF-1 was 19.2 (8.0) μg/l (treated) and 15.4 (4.7) μg/l (controls). Mean (SD) IGF-1 increased to 45.9 (19.6) μg/l at 12 h in treated infants, and remained within target levels for all subsequent timepoints. For treated infants, 88.8% of the IGF-1 measurements were within target levels (controls, 11.1%).
  
  
  
  Through the reported work, we determined appropriate rhIGF-1/rhIGFBP-3 dosing to achieve physiological intrauterine serum IGF-1 levels in extremely preterm infants.
authors.affiliation: Shire, Lexington, Massachusetts.
authors.forename: Jou-Ku
authors.initials: JK
authors.lastname: Chung
authors.affiliation: Department of Neonatology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Boubou
authors.initials: B
authors.lastname: Hallberg
authors.affiliation: Department of Clinical Sciences Lund, Pediatrics, Skåne University Hospital, Lund University, Lund, Sweden.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Hansen-Pupp
authors.affiliation: KinderPharm/PKPD Bioscience Inc., Exton, Pennsylvania.
authors.forename: Martin A
authors.initials: MA
authors.lastname: Graham
authors.affiliation: KinderPharm/PKPD Bioscience Inc., Exton, Pennsylvania.
authors.forename: Gerald
authors.initials: G
authors.lastname: Fetterly
authors.affiliation: KinderPharm/PKPD Bioscience Inc., Exton, Pennsylvania.
authors.forename: Jyoti
authors.initials: J
authors.lastname: Sharma
authors.affiliation: Shire, Zug, Switzerland.
authors.forename: Adina
authors.initials: A
authors.lastname: Tocoian
authors.affiliation: Shire, Lexington, Massachusetts.
authors.forename: Nerissa C
authors.initials: NC
authors.lastname: Kreher
authors.affiliation: Shire, Lexington, Massachusetts.
authors.forename: Norman
authors.initials: N
authors.lastname: Barton
authors.affiliation: Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
authors.forename: Ann
authors.initials: A
authors.lastname: Hellström
authors.affiliation: Department of Clinical Sciences Lund, Pediatrics, Skåne University Hospital, Lund University, Lund, Sweden.
authors.forename: David
authors.initials: D
authors.lastname: Ley
mesh_terms: D001786:Blood Glucose; D003198:Computer Simulation; D005260:Female; D005865:Gestational Age; D006801:Humans; D062071:Infant, Extremely Premature; D007231:Infant, Newborn; D007234:Infant, Premature; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000097:blood*; D007334:Insulin-Like Growth Factor I / Q000627:therapeutic use*; D008297:Male; D011994:Recombinant Proteins / Q000097:blood* / Q000627:therapeutic use*; D012016:Reference Values; D013997:Time Factors
chemical_list: D001786:Blood Glucose; D018972:Insulin-Like Growth Factor Binding Protein 3; D011994:Recombinant Proteins; D007334:Insulin-Like Growth Factor I