title: Pharmacokinetic and Pharmacodynamic Modeling of MOD-4023, a Long-Acting Human Growth Hormone, in Growth Hormone Deficiency Children.
abstract: OBJECTIVE
  MOD-4023 is a long-acting human growth hormone (hGH) in clinical trials for the treatment of growth hormone deficiency (GHD). A key goal is maintenance of serum concentrations of insulin-like growth factor (IGF) 1 within normal range throughout GH dosing. The study aimed to develop a pharmacokinetic model for MOD-4023 and a pharmacodynamic model for the effect of MOD-4023 on IGF-1 to allow estimation of peak and mean IGF-1 and to identify the optimal IGF-1 sampling day.
  
  
  METHODS
  MOD-4023 (0.25, 0.48, or 0.66 mg/kg) was administered weekly for 12 months to 41 GH-naive GHD children (age 3-11 years). The control group (n = 11, age 4-9 years) received daily recombinant human growth hormone (r-hGH; 34 µg/kg). Sparse samples (4/subject) were obtained to determine serum concentrations of MOD-4023 or r-hGH and IGF-1.
  
  
  RESULTS
  A 2-compartment pharmacokinetic model with first-order absorption fit MOD-4023 data well; a 1-compartment model was appropriate for r-hGH. For both, weight-normalized systemic parameters were preferred over allometric scaling. For MOD-4023, an indirect model fit IGF-1 SDS data well; baseline IGF-1 increased over time. At steady state, samples obtained 4 days following dose administration predicted mean IGF-1 SDS during the dosing interval well.
  
  
  CONCLUSIONS
  The IGF-1 profile is consistent with the weekly dosing interval. Sampling 4 days following dose administration allows estimation of mean IGF-1 SDS during the dosing interval in GHD patients.
authors.affiliation: P Less Than, San Francisco, California, USA.
authors.forename: Dennis M
authors.initials: DM
authors.lastname: Fisher
authors.affiliation: Stat5 Consulting, LLC, Los Altos, California, USA.
authors.forename: Ron G
authors.initials: RG
authors.lastname: Rosenfeld
authors.affiliation: OPKO Biologics, Kiryat Gat, Israel.
authors.forename: Michal
authors.initials: M
authors.lastname: Jaron-Mendelson
authors.affiliation: OPKO Biologics, Kiryat Gat, Israel.
authors.forename: Leanne
authors.initials: L
authors.lastname: Amitzi
authors.affiliation: OPKO Biologics, Kiryat Gat, Israel.
authors.forename: Ronit
authors.initials: R
authors.lastname: Koren
authors.affiliation: OPKO Biologics, Kiryat Gat, Israel.
authors.forename: Gili
authors.initials: G
authors.lastname: Hart
mesh_terms: D002648:Child; D002675:Child, Preschool; D005260:Female; D019382:Human Growth Hormone / Q000008:administration & dosage / Q000172:deficiency / Q000493:pharmacokinetics; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D008297:Male; D008954:Models, Biological
chemical_list: C583557:IGF1 protein, human; D019382:Human Growth Hormone; D007334:Insulin-Like Growth Factor I
keywords: Growth hormone; Growth hormone deficiency; Growth hormone replacement; Growth in children; Insulin growth factor 1; Long-acting growth hormone; Pharmacokinetic/pharmacodynamic modeling; Weekly growth hormone