Pharmacokinetic and Pharmacodynamic Modeling of MOD-4023, a Long-Acting Human Growth Hormone, in Growth Hormone Deficiency Children

Dennis M. Fisher, Ronald (Ron) Rosenfeld, Michal Jaron-Mendelson, Leanne Amitzi, Ronit Koren, Gili Hart

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Background/Aims: 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. Conclusion: 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.

Original languageEnglish (US)
Pages (from-to)324-332
Number of pages9
JournalHormone Research in Paediatrics
Volume87
Issue number5
DOIs
StatePublished - Jul 1 2017
Externally publishedYes

Fingerprint

Human Growth Hormone
Somatomedins
Growth Hormone
Pharmacokinetics
Serum
varespladib methyl
Reference Values
Maintenance
Clinical Trials
Weights and Measures
Control Groups

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

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

Cite this

Pharmacokinetic and Pharmacodynamic Modeling of MOD-4023, a Long-Acting Human Growth Hormone, in Growth Hormone Deficiency Children. / Fisher, Dennis M.; Rosenfeld, Ronald (Ron); Jaron-Mendelson, Michal; Amitzi, Leanne; Koren, Ronit; Hart, Gili.

In: Hormone Research in Paediatrics, Vol. 87, No. 5, 01.07.2017, p. 324-332.

Research output: Contribution to journalArticle

Fisher, Dennis M. ; Rosenfeld, Ronald (Ron) ; Jaron-Mendelson, Michal ; Amitzi, Leanne ; Koren, Ronit ; Hart, Gili. / Pharmacokinetic and Pharmacodynamic Modeling of MOD-4023, a Long-Acting Human Growth Hormone, in Growth Hormone Deficiency Children. In: Hormone Research in Paediatrics. 2017 ; Vol. 87, No. 5. pp. 324-332.
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T1 - Pharmacokinetic and Pharmacodynamic Modeling of MOD-4023, a Long-Acting Human Growth Hormone, in Growth Hormone Deficiency Children

AU - Fisher, Dennis M.

AU - Rosenfeld, Ronald (Ron)

AU - Jaron-Mendelson, Michal

AU - Amitzi, Leanne

AU - Koren, Ronit

AU - Hart, Gili

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N2 - Background/Aims: 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. Conclusion: 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.

AB - Background/Aims: 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. Conclusion: 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.

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KW - Growth hormone deficiency

KW - Growth hormone replacement

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KW - Insulin growth factor 1

KW - Long-Acting growth hormone

KW - Pharmacokinetic/pharmacodynamic modeling

KW - Weekly growth hormone

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