Non-clinical pharmacology and safety evaluation of TH9507, a human growth hormone-releasing factor analogue.

TH9507, an analogue of human growth hormone-releasing factor (hGRF1-44NH2) minimally modified by addition of a trans-3-hexenoyl moiety to Tyr1 of the amino acid sequence, was found to be resistant to dipeptidyl aminopeptidase-IV deactivation. Compared to natural hGRF1-44NH2, 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 microg/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 t1/2 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.

Impact of Tesamorelin, a Growth Hormone-Releasing Factor (GRF) Analogue, on the Pharmacokinetics of Simvastatin and Ritonavir in Healthy Volunteers.

The potential impact of tesamorelin on CYP3A activity was investigated by examining its effect on the pharmacokinetics of simvastatin and ritonavir. In two randomized, two-way crossover studies, subjects were administered 2 mg tesamorelin on Days 1-7 with 80 mg simvastatin or 100 mg ritonavir co-administered on Day 6 (Treatment A), and a single dose of simvastatin or ritonavir alone on Day 6 (Treatment B). Pharmacokinetic samples were collected on Day 6 to measure simvastatin, ritonavir and tesamorelin plasma concentrations. For simvastatin, A/B ratios of least squares geometric means and corresponding 90% confidence intervals (CIs) for AUC0-t , AUC0-inf and Cmax were contained within the usual no effect range of 80-125%. For ritonavir, ratios and 90% CIs for AUCs were within this acceptance range, but the lower CI for Cmax was 74.8%, suggesting a decreased rate of exposure. However, since the A/B ratios for AUCs and Cmax parameters were approximately 90%, these were minor decreases and no dose adjustment of ritonavir is required in the presence of tesamorelin. These studies showed that the impact of tesamorelin on CYP3A activity appears to be minimal, if any. Either medication may be co-administered with tesamorelin in patients without changing their original dosing regimen.