title: Osilodrostat (LCI699), a potent 11β-hydroxylase inhibitor, administered in combination with the multireceptor-targeted somatostatin analog pasireotide: A 13-week study in rats.
abstract: 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 (0.3mg/kg/day, subcutaneously), osilodrostat (20mg/kg/day, orally), osilodrostat/pasireotide in combination (low dose, 1.5/0.03mg/kg/day; mid-dose, 5/0.1mg/kg/day; or high dose, 20/0.3mg/kg/day), or vehicle for 13weeks. 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. Cmax and AUC0-24h of osilodrostat and pasireotide increased in an approximately dose-proportional manner. 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.
authors.affiliation: Preclinical Safety, Novartis Institutes for BioMedical Research, East Hanover, NJ, USA. Electronic address: li1.li@novartis.com.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: Preclinical Safety, Novartis Institutes for BioMedical Research, East Hanover, NJ, USA.
authors.forename: Kapil
authors.initials: K
authors.lastname: Vashisht
authors.affiliation: Preclinical Safety, Novartis Institutes for BioMedical Research, East Hanover, NJ, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Boisclair
authors.affiliation: Drug Metabolism and Pharmacokinetics, Novartis Institutes for BioMedical Research, East Hanover, NJ, USA.
authors.forename: Wenkui
authors.initials: W
authors.lastname: Li
authors.affiliation: Drug Metabolism and Pharmacokinetics, Novartis Institutes for BioMedical Research, East Hanover, NJ, USA.
authors.forename: Tsu-Han
authors.initials: TH
authors.lastname: Lin
authors.affiliation: Novartis Oncology Development, Basel, Switzerland.
authors.forename: Herbert A
authors.initials: HA
authors.lastname: Schmid
authors.affiliation: Preclinical Safety, Novartis Institutes for BioMedical Research, East Hanover, NJ, USA.
authors.forename: William
authors.initials: W
authors.lastname: Kluwe
authors.affiliation: Preclinical Safety, Novartis Institutes for BioMedical Research, East Hanover, NJ, USA.
authors.forename: Heidi
authors.initials: H
authors.lastname: Schoenfeld
authors.affiliation: Preclinical Safety, Novartis Institutes for BioMedical Research, East Hanover, NJ, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Hoffmann
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D016503:Drug Delivery Systems / Q000379:methods; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D005260:Female; D007093:Imidazoles / Q000008:administration & dosage*; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008297:Male; D009929:Organ Size / Q000187:drug effects / Q000502:physiology; D011725:Pyridines / Q000008:administration & dosage*; D051381:Rats; D017208:Rats, Wistar; D013004:Somatostatin / Q000008:administration & dosage* / Q000031:analogs & derivatives*; D013252:Steroid 11-beta-Hydroxylase / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D004338:Drug Combinations; D004791:Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; D013004:Somatostatin; C553306:Osilodrostat; C517782:pasireotide; D013252:Steroid 11-beta-Hydroxylase
keywords: 11β-hydroxylase; LCI699; Osilodrostat; Pasireotide; Preclinical; Somatostatin