Pharmacology & toxicology

Nonclinical pharmacology and toxicology highlights.

Pharmacologic effect

Inpegsomatropin is a pegylated growth hormone, which exerts equivalent pharmacological activity to endogenous human growth hormone.

The primary action of growth hormone is to stimulate skeletal and somatic growth, with significant effects on metabolic processes in the body.

Correction of growth hormone deficiency leads to normalization of body composition—increased lean body mass and reduced body fat mass.

Growth hormone mediates its effects predominantly through IGF-1, produced in tissues throughout the body but predominantly by the liver. Over 90% of IGF-1 binds to IGF-binding proteins (IGFBPs), most notably IGFBP-3.

During metabolic stress, GH exhibits critical lipolytic and protein-sparing effects.

GH can enhance bone turnover (biochemical markers). In adults, initial GH therapy may transiently reduce bone mass due to increased resorption; with continued treatment, bone mass increases.

Genotoxicity

Pegpesen^® demonstrated negative results in the in vitro Ames test, chromosomal aberration test in CHL cells, and in vivo micronucleus test in mice.

Reproductive toxicity (summary)

In rats at SC doses 1, 3, 10 mg/kg (exposure multiples cited relative to pediatric 0.14 mg/kg), prolonged estrous cycles were seen in females at 10 mg/kg; no major fertility or early embryonic effects in males/females at tested doses.

Embryo-fetal studies at 0.4, 1.6, 6.4 mg/kg on gestation days 6 & 12: no maternal toxicity, embryo-fetal toxicity, or teratogenicity; NOAEL 6.4 mg/kg (~7.4× human dose on BSA basis, as reported).

Perinatal study in rats: no effects on F0/F1 growth, neurobehavior, reproduction, or F2 survival at doses up to ~6.1× human exposure (as reported).

Pegpesen^® can cross the placental and blood–milk barriers; fetal/pup exposure increases with dose.

Carcinogenicity

No carcinogenicity studies have been conducted on Pegpesen^®.