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Title: Osilodrostat (LCI699), a potent 11β-hydroxylase inhibitor, administered in combination with the multireceptor-targeted somatostatin analog pasireotide: A 13-week study in rats

The somatostatin analog pasireotide and the 11β-hydroxylase inhibitor osilodrostat (LCI699) reduce cortisol levels by distinct mechanisms of action. There exists a scientific rationale to investigate the clinical efficacy of these two agents in combination. This manuscript reports the results of a toxicology study in rats, evaluating different doses of osilodrostat and pasireotide alone and in combination. Sixty male and 60 female rats were randomized into single-sex groups to receive daily doses of pasireotide (0.3 mg/kg/day, subcutaneously), osilodrostat (20 mg/kg/day, orally), osilodrostat/pasireotide in combination (low dose, 1.5/0.03 mg/kg/day; mid-dose, 5/0.1 mg/kg/day; or high dose, 20/0.3 mg/kg/day), or vehicle for 13 weeks. Mean body-weight gains from baseline to Week 13 were significantly lower in the pasireotide-alone and combined-treatment groups compared to controls, and were significantly higher in female rats receiving osilodrostat monotherapy. Osilodrostat and pasireotide monotherapies were associated with significant changes in the histology and mean weights of the pituitary and adrenal glands, liver, and ovary/oviduct. Osilodrostat alone was associated with adrenocortical hypertrophy and hepatocellular hypertrophy. In combination, osilodrostat/pasireotide did not exacerbate any target organ changes and ameliorated the liver and adrenal gland changes observed with monotherapy. C{sub max} and AUC{sub 0–24h} of osilodrostat and pasireotide increased in an approximately dose-proportional manner.more » In conclusion, the pasireotide and osilodrostat combination did not exacerbate changes in target organ weight or toxicity compared with either monotherapy, and had an acceptable safety profile; addition of pasireotide to the osilodrostat regimen may attenuate potential adrenal gland hyperactivation and hepatocellular hypertrophy, which are potential side effects of osilodrostat monotherapy. - Highlights: • We examined the target organ toxicity of SOM230 (pasireotide) and LCI699 (osilodrostat) alone or in combination. • Co-treatment with pasireotide and osilodrostat did not exacerbate target organ toxicity by either compound. • Co-treatment with pasireotide and osilodrostat did not change the systemic exposure of either compound. • Combination of pasireotide and osilodrostat appeared to ameliorate some of the target organ effects by either compound.« less
Authors:
 [1] ; ;  [1] ; ;  [2] ;  [3] ; ; ;  [1]
  1. Preclinical Safety, Novartis Institutes for BioMedical Research, East Hanover, NJ (United States)
  2. Drug Metabolism and Pharmacokinetics, Novartis Institutes for BioMedical Research, East Hanover, NJ (United States)
  3. Novartis Oncology Development, Basel (Switzerland)
Publication Date:
OSTI Identifier:
22465798
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 286; Journal Issue: 3; Other Information: Copyright (c) 2015 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ACTH; ADRENAL GLANDS; COMPARATIVE EVALUATIONS; DOSES; GROWTH FACTORS; HISTOLOGY; HYDROCORTISONE; HYDROXYLASES; HYPERTROPHY; INSULIN; LIVER; OVARIES; RATS; RECEPTORS; SIDE EFFECTS; SOMATOSTATIN; STH; TOXICITY; WEIGHT