title: Pegylated long-acting human growth hormone is well-tolerated in healthy subjects and possesses a potential once-weekly pharmacokinetic and pharmacodynamic treatment profile.
abstract: BACKGROUND
  Recombinant human GH (rhGH) is usually administered as a daily sc injection, which may be both inconvenient and distressing for patients. NNC126-0083 is a pegylated rhGH developed with the aim of reducing serum clearance and thereby prolonging the exposure leading to once-weekly sc administration.
  
  
  OBJECTIVE
  In this first human dose trial, the safety, tolerability, pharmacokinetics, and pharmacodynamic parameters of a single administration of NNC126-0083 were evaluated.
  
  
  METHODS
  Seven groups of eight healthy male volunteers were dosed once with a single sc administration of NNC126-0083 (n = 6) or placebo (n = 2). The doses were escalated between the cohorts in a sequential mode. Blood samples for assessment of safety, pharmacokinetics, and pharmacodynamic response (IGF-I, IGF binding protein-3, free IGF-I) as well as GH binding protein were taken up to 240 h after dosing.
  
  
  RESULTS
  Seven doses of NNC126-0083 were administered. After NNC126-0083 administration, a significant deviation from pharmacokinetic dose proportionality was observed for the highest doses. A strong dose-dependent pharmacodynamic response was seen with elevated levels of IGF-I and IGF binding protein-3 for all doses administered. The elevation was maintained for more than 1 wk for the highest doses. All doses of NNC126-0083 were well tolerated. No local tolerability issues were identified.
  
  
  CONCLUSIONS
  After a single sc administration of NNC126-0083 in healthy male volunteers, a sustained dose-dependent pharmacodynamic response was induced. These results indicate that NNC126-0083 has the potential for an efficacious, well-tolerated, once-weekly rhGH compound in the treatment of GH deficiency in adults.
authors.affiliation: Departments of Medical and Science, Novo Nordisk A/S, DK 2880 Bagsvaerd, Denmark. mhr@novonordisk.com
authors.forename: Michael Højby
authors.initials: MH
authors.lastname: Rasmussen
authors.forename: Britta V
authors.initials: BV
authors.lastname: Bysted
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Anderson
authors.forename: Thomas
authors.initials: T
authors.lastname: Klitgaard
authors.forename: Jesper
authors.initials: J
authors.lastname: Madsen
mesh_terms: D000328:Adult; D000704:Analysis of Variance; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004797:Enzyme-Linked Immunosorbent Assay; D019382:Human Growth Hormone / Q000008:administration & dosage* / Q000009:adverse effects* / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000097:blood; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008297:Male; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects
chemical_list: D018972:Insulin-Like Growth Factor Binding Protein 3; D011994:Recombinant Proteins; D019382:Human Growth Hormone; D007334:Insulin-Like Growth Factor I