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Non‐Clinical Pharmacology and Safety Evaluation of TH9507, a Human Growth Hormone‐Releasing Factor Analogue
Author(s) -
Ferdinandi Eckhardt S.,
Brazeau Paul,
High Kim,
Procter Bryan,
Fennell Stephen,
Dubreuil Pascal
Publication year - 2007
Publication title -
basic and clinical pharmacology and toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.805
H-Index - 90
eISSN - 1742-7843
pISSN - 1742-7835
DOI - 10.1111/j.1742-7843.2007.00008.x
Subject(s) - potency , endocrinology , medicine , toxicity , in vivo , subcutaneous injection , adverse effect , hormone , pharmacology , pharmacokinetics , chemistry , in vitro , biology , biochemistry , microbiology and biotechnology
TH9507, an analogue of human growth hormone‐releasing factor (hGRF(1–44)NH 2 ) minimally modified by addition of a trans ‐3‐hexenoyl moiety to Tyr 1 of the amino acid sequence, was found to be resistant to dipeptidyl aminopeptidase‐IV deactivation. Compared to natural hGRF(1–44)NH 2 , the modification slowed the in vitro degradation of the peptide in rat, dog and human plasma and prolonged the in vivo plasma elimination kinetics of immunoreactive TH9507. Plasma growth hormone and insulin‐like growth factor‐1 (IGF‐1) markedly increased in pigs, rats and dogs after daily repeat intravenous or subcutaneous injections of TH9507 at doses up to 600 µg/kg. Subchronic toxicity studies in rats and dogs with TH9507 treatment for up to 4 months showed a significant, but not dose‐related, increase in body weight gain associated with increased biomarker response. Although TH9507 was well tolerated by both rats and dogs, a more pronounced anabolic effect and more evident (reversible) adverse effects (liver and kidney findings, anaemia, clinical chemistry changes, organ weight effects) were observed in dogs after repeat daily subcutaneous injections, which were attributed to prolonged exposure to supraphysiological levels of growth hormone and/or IGF‐1. In both rats and dogs, toxicokinetic evaluations indicated that exposure to immunoreactive TH9507 was dose related after both routes of administration. The apparent elimination t 1/2 in dogs ranged from 21 to 45 min. In conclusion, TH9507 is a modified hGRF peptide having enhanced potency and duration of action. The adverse treatment‐related effects in dogs appear to be associated with sustained exposure to supraphysiological levels of growth hormone and IGF‐1 induced by prolonged TH9507 treatment.