title: Pharmacokinetic studies of recombinant human insulin-like growth factor I (rhIGF-I)/rhIGF-binding protein-3 complex administered to patients with growth hormone insensitivity syndrome.
abstract: BACKGROUND
  GH insensitivity syndrome (GHIS), Laron syndrome, is characterized by severe short stature, high serum GH levels, and very low serum IGF-I and IGF-binding protein-3 (IGFBP-3) levels associated with a genetic defect of the GH receptor. Recombinant human (rh) IGF-I treatment at doses of 80-120 microg/kg given sc twice daily is effective in promoting growth in these patients. We have investigated a newly developed drug, rhIGF-I/rhIGFBP-3, a 1:1 molar complex of rhIGF-I and rhIGFBP-3.
  
  
  OBJECTIVE
  The objectives of the study were to determine IGF-I pharmacokinetics after the administration of rhIGF-I/rhIGFBP-3 in adolescents with GHIS and to evaluate its safety and tolerability.
  
  
  METHODS
  This was an open-label clinical study.
  
  
  METHODS
  The study was conducted in a general pediatric ward of a university teaching hospital.
  
  
  METHODS
  Four patients (one female and three males; mean age, 14.9 yr; mean height sd score, -4.9) with confirmed molecular diagnosis of GHIS agreed to participate in the study.
  
  
  METHODS
  rhIGF-I/rhIGFBP-3 was administered in a single sc injection at 0.5 and 1.0 mg/kg.dose (equivalent to 100 and 200 microg/kg rhIGF-I) after breakfast with a 2-d interval between doses.
  
  
  RESULTS
  IGF-I levels reached a maximum between 19 +/- 8.3 and 15 +/- 6.2 h for the low and high doses, respectively. The circulating IGF-I levels obtained with the low and high doses were similar, although a discrete dose-dependent increase in circulating IGF-I levels was observed. The IGF-I half-life in four subjects after a dose of 0.5 mg/kg rhIGF-I/rhIGFBP-3 was estimated to be 21+/- 4 h. There were no acute adverse events reported, and all blood glucose measurements were normal.
  
  
  CONCLUSIONS
  These data demonstrated that the rhIGF-I/rhIGFBP-3 complex was effective in increasing levels of circulating total and free IGF-I into the normal range for a 24-h period after a single sc administration in patients with GHIS, and that administration of rhIGF-I/rhIGFBP-3 was safe and well tolerated.
authors.affiliation: Department of Endocrinology, William Harvey Research Institute, John Vane Science Building, First Floor, Charterhouse Square, London EC1M 6BQ, United Kingdom. c.camacho-hubner@qmul.ac.uk
authors.forename: Cecilia
authors.initials: C
authors.lastname: Camacho-Hübner
authors.forename: Stephen
authors.initials: S
authors.lastname: Rose
authors.forename: Michael A
authors.initials: MA
authors.lastname: Preece
authors.forename: Mark
authors.initials: M
authors.lastname: Sleevi
authors.forename: Helen L
authors.initials: HL
authors.lastname: Storr
authors.forename: Farideh
authors.initials: F
authors.lastname: Miraki-Moud
authors.forename: Francesco
authors.initials: F
authors.lastname: Minuto
authors.forename: Jan
authors.initials: J
authors.lastname: Frystyk
authors.forename: Alan
authors.initials: A
authors.lastname: Rogol
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Allan
authors.forename: Andreas
authors.initials: A
authors.lastname: Sommer
authors.forename: Martin O
authors.initials: MO
authors.lastname: Savage
mesh_terms: D000293:Adolescent; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D015992:Body Mass Index; D002352:Carrier Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D006023:Glycoproteins / Q000378:metabolism; D019382:Human Growth Hormone / Q000502:physiology*; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D007334:Insulin-Like Growth Factor I / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D007335:Insulin-Like Growth Factor II / Q000378:metabolism; D046150:Laron Syndrome / Q000378:metabolism*; D008297:Male; D015233:Models, Statistical; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: D001786:Blood Glucose; D002352:Carrier Proteins; D006023:Glycoproteins; D018972:Insulin-Like Growth Factor Binding Protein 3; D011994:Recombinant Proteins; C075944:insulin-like growth factor binding protein, acid labile subunit; D019382:Human Growth Hormone; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II