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

Li, Li and Vashisht, Kapil and Boisclair, Julie and Li, Wenkui and Lin, Tsu-Han and Schmid, Herbert and Kluwe, William and Schoenfeld, Heidi and Hoffmann, Peter (2015) LCI699, a potent 11β-hydroxylase inhibitor, administered in combination with the multireceptor-targeted somatostatin analog pasireotide: A 13-week study in rats. Toxicology and Applied Pharmacology, 286 (3). pp. 224-233. ISSN 0041008X

Abstract

The somatostatin analog pasireotide and the 11β-hydroxylase inhibitor LCI699 reduce cortisol levels by distinct mechanisms of action. As such, 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 LCI699 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), LCI699 (20 mg/kg/day, orally), LCI699/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 LCI699 monotherapy. LCI699 and pasireotide monotherapies were associated with significant changes in the histology and mean weights of the pituitary and adrenal glands, liver, and ovary/oviduct. LCI699 alone was associated with adrenocortical hypertrophy and hepatocellular hypertrophy. In combination, LCI699/pasireotide did not exacerbate any target organ changes and ameliorated the liver and adrenal gland changes observed with monotherapy. Cmax and AUC0–24h of LCI699 and pasireotide increased in an approximately dose-proportional manner. The pasireotide and LCI699 combination did not exacerbate changes in target organ weight or toxicity compared with either monotherapy, and had an acceptable safety profile; the addition of pasireotide to the LCI699 regimen may attenuate potential adrenal gland hyperactivation and hepatocellular hypertrophy, which are potential side effects of LCI699 monotherapy.

Item Type: Article
Keywords: Pasireotide, somatostatin, LCI699, 11β-hydroxylase, Cushing’s, preclinical
Date Deposited: 26 Apr 2016 23:45
Last Modified: 26 Apr 2016 23:45
URI: https://oak.novartis.com/id/eprint/24076

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