Cortisol and aldosterone are inhibited by osilodrostat (LCI699; 0.01-10 μM; HAC15 cells, 17 primary human adrenocortical cell cultures, pituitary adenoma cells). Osilodrostat has minor effects on adrenal androgens and suppresses the build-up of corticosterone and 11-deoxycortisol [2].

In Ang-II and ACTH-stimulated Sprague Dawley rats, osilodrostat (LCI699; 0.1-100 mg/kg; oral; once) inhibits the synthesis of aldosterone and corticosterone [1]. Osilodrostat (LCI699; 3-100 mg/kg; oral; once daily for 52 weeks) prolongs the survival of dTG rats by lowering mean arterial pressure [1].

Animal/Disease Models: Male Ang-II- and ACTH-stimulated Sprague Dawley rats[1]
Doses: 0.1, 0.3, 1 and 3 mg/kg (Ang-II-stimulated rats) and 1, 3, 10, 30 and 100 mg/ kg (ACTH-stimulated rats)
Route of Administration: Oral administration; once
Experimental Results: Inhibited the increase in plasma aldosterone concentrations stimulated by Ang II or ACTH in a dose-dependent manner.

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Animal/Disease Models: dTG rats[1]
Doses: 3, 10, 30 and 100 mg/kg
Route of Administration: Oral administration; daily, for 52 weeks
Experimental Results: Increased fractional LV (systolic and diastolic) shortening, normalized LV isovolumic relaxation time to RR (IVRT/RR) ratio and myocardial cell size and decreased LV weight in a dose-dependent manner.

Absorption, Distribution and Excretion
The oral absorption of osilodrostat is rapid, with a Tmax of approximately 1 hour, and assumed to be essentially complete. Exposure (i.e. AUC and Cmax) increases slightly more than dose-proportionately over the standard dosing range. Coadministration of osilodrostat with food does not affect its pharmacokinetics to a clinically significant extent. Age and gender do not affect pharmacokinetics, but bioavailability and total exposure is higher (though not clinically significant) in patients of Asian descent. Exposure to osilodrostat is greater in patients with moderate-severe hepatic impairment - prescribing information recommends a starting dose of 1mg twice daily in patients with moderate hepatic impairment (Child-Pugh B) and a starting dose of 1mg each evening in patients with severe hepatic impairment (Child-Pugh C).
Following oral administration of radiolabeled osilodrostat, 90.6% of the radioactivity was eliminated in the urine with only 1.58% in the feces. Only 5.2% of the administered dose was eliminated in the urine as unchanged parent drug, suggesting that metabolism followed by urinary elimination is osildrostat's primary means of clearance.
The median apparent volume of distribution of osilodrostat is 100 L.
Data regarding the oral clearance of osilodrostat are not currently available.

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Metabolism / Metabolites
Osilodrostat is extensively metabolized - approximately 80% of an orally administered dose is excreted as metabolites, and this is the predominant means of drug clearance. The most abundant metabolites in plasma are M35.4 (di-oxygenated osilodrostat), M16.5, and M24.9 at 51%, 9%, and 7% of the administered dose, respectively. The M34.5 and M24.9 metabolites have longer half-lives than the parent drug which may lead to accumulation with twice-daily dosing. Of the thirteen metabolites observed in the urine, the most abundant are M16.5 (osilodrostat glucuronide), M22 (a glucuronide conjugate of M34.5), and M24.9 at 17%, 13%, and 11% of the administered dose, respectively. The M34.5 metabolite accounts for less than 1% of the dose excreted in urine, but its glucuronide conjugate (M22) accounts for approximately 13%. The biotransformation of osilodrostat is mediated by multiple cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT) enzymes, though no single enzyme appears to contribute >25% to the total clearance. Of the total clearance, approximately 26% is CYP-mediated, 19% is UGT-mediated, and 50% is mediated by other enzymes. The formation of M34.5, the major metabolite of osilodrostat, is likely non-CYP-mediated. The formation of osilodrostat glucuronide (M16.5), its major urinary metabolite, is catalyzed by UGT1A4, UGT2B7, and UGT2B10. _In vitro_ data suggest that none of the metabolites contribute to the therapeutic efficacy of osilodrostat, but the M34.5 metabolite has been implicated in the inhibition and/or induction of multiple enzymes and transporters.

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Biological Half-Life
The elimination half-life of osilodrostat is approximately 4 hours.

Hepatotoxicity
In preregistration trials, mild, transient serum aminotransferase elevations occurred in 37 of 137 (27%) patients receiving osilodrostat for Cushing disease, but in only 8 (6%) patients were values above 3 times the upper limit of normal (ULN), and only 1 was above 5 times ULN (
Likelihood score: E (unlikely cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No information is available on the use of osilodrostat during breastfeeding. Because of the potential for serious adverse reactions, such as adrenal insufficiency, in the breastfed infant, breastfeeding is not recommended during treatment with osilodrostat and should be avoided until 1 week after the final dose.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
Both osilodrostat and its M34.5 metabolite are minimally protein-bound in plasma at less than 40%. The extent of protein-binding is independent of drug concentration. The specific plasma proteins to which osilodrostat binds have not been elucidated.

[1]. Aldosterone synthase inhibition: cardiorenal protection in animal disease models and translation of hormonal effects to human subjects. J Transl Med. 2014 Dec 10;12:340.

[2]. Osilodrostat Is a Potential Novel Steroidogenesis Inhibitor for the Treatment of Cushing Syndrome: An In Vitro Study. J Clin Endocrinol Metab. 2019 Aug 1;104(8):3437-3449.

[3]. Osilodrostat (LCI699), a potent 11β-hydroxylase inhibitor, administered in combination with the multireceptor-targeted somatostatin analog pasireotide: A 13-week study in rats. Toxicol Appl Pharmacol. 2015 Aug 1;286(3):224-33.

Osilodrostat is an inhibitor of 11β-hydroxylase (also referred to as CYP11B1), the enzyme that catalyzes the final step in the biosynthesis of endogenous cortisol. It is used to lower circulating cortisol levels in the treatment of Cushing's disease, a disorder in which cortisol levels are chronically and supraphysiologically elevated. Cushing's disease is often the result of ACTH hypersecretion secondary to a pituitary tumor, and surgical resection of the tumour is generally the treatment of choice. As an orally bioavailable drug therapy, osilodrostat provides a novel treatment option for patients in whom removal of the causative tumor is not an option or for whom previous pituitary surgery has not been curative. Osilodrostat is manufactured by Novartis under the brand name Isturisa. It has undergone phase II clinical trials for the treatment of solid tumours, hypertension, and heart failure, but development for these indications was discontinued by Novartis in January 2013. Osilodrostat was approved for use in the EU in January 2020 for the treatment of endogenous Cushing's syndrome (i.e. Cushing's disease), and was granted FDA approval and Orphan Drug designation in the US in March 2020 for the same indication.
Osilodrostat is a Cortisol Synthesis Inhibitor. The mechanism of action of osilodrostat is as a Cytochrome P450 11B1 Inhibitor, and Cytochrome P450 1A2 Inhibitor, and Cytochrome P450 2C19 Inhibitor, and Cytochrome P450 2D6 Inhibitor, and Cytochrome P450 3A4 Inhibitor, and Cytochrome P450 3A5 Inhibitor.
Osilodrostat is an inhibitor of cortisol synthesis that is used in the treatment of Cushing disease not controlled by standard therapy. Osilodrostat therapy has not been linked to serum aminotransferase elevations during therapy or with instances of clinically apparent liver injury.
Osilodrostat is an orally bioavailable inhibitor of both steroid 11beta-hydroxylase (cytochrome P450 (CYP) 11B1) and aldosterone synthase (CYP11B2; steroid 18-hydroxylase), with potential anti-adrenal activity and ability to treat Cushing disease (CD). Upon administration, osilodrostat binds to and inhibits the activity of CYP11B1, the enzyme that catalyzes the final step of cortisol synthesis from the precursor 11-deoxycortisol, and CYP11B2, the enzyme that catalyzes aldosterone synthesis from corticosterone and 11-deoxycorticosterone in the adrenal gland. The inhibition of CYP11B1 prevents the production of excess cortisol, thereby decreasing and normalizing the levels of cortisol. CD is most often caused by an adrenocorticotropic hormone (ACTH)-secreting pituitary tumor.
See also: Osilodrostat Phosphate (active moiety of).

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Drug Indication
Osilodrostat is indicated for the treatment of adult patients with Cushing's disease for whom pituitary surgery is not an option or has not been curative.
FDA Label
Isturisa is indicated for the treatment of endogenous Cushing's syndrome in adults.
Treatment of adrenal cortical hyperfunction

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Mechanism of Action
Cushing’s syndrome is an endocrine disorder resulting from chronic and excessive exposure to glucocorticoids, the symptoms of which may include thinning of the skin and hair, weight gain, muscle weakness, and osteoporosis, as well a constellation of psychiatric, cardiovascular, and immunological deficiencies. Cushing’s syndrome is most commonly precipitated by exogenous treatment with supraphysiological doses of glucocorticoids such as those found in nasal sprays, skin creams, and inhalers. Cushing’s disease - another less common cause of Cushing’s syndrome - is generally the result of increased endogenous cortisol exposure due to excessive secretion of adrenocroticotrophic hormone (ACTH) from a pituitary adenoma. Osilodrostat is an inhibitor of 11β-hydroxylase (CYP11B1) and, to a lesser extent, aldosterone synthase (CYP11B2). The CYP11B1 enzyme is responsible for catalyzing the final step of cortisol synthesis - by inhibiting this enzyme, osilodrostat helps to normalize endogenous cortisol levels and alleviate symptoms of Cushing’s disease.

C13H10FN3

227.24

227.085

928134-65-0

Osilodrostat phosphate;1315449-72-9

44139752

White to yellow solid powder

1.3±0.1 g/cm3

433.8±45.0 °C at 760 mmHg

216.2±28.7 °C

0.0±1.0 mmHg at 25°C

1.664

1.13

0

3

1

17

337

1

C1CC2=CN=CN2[C@H]1C3=C(C=C(C=C3)C#N)F

USUZGMWDZDXMDG-CYBMUJFWSA-N

InChI=1S/C13H10FN3/c14-12-5-9(6-15)1-3-11(12)13-4-2-10-7-16-8-17(10)13/h1,3,5,7-8,13H,2,4H2/t13-/m1/s1

4-[(5R)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl]-3-fluorobenzonitrile

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (11.00 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (11.00 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (11.00 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: ≥ 2.5 mg/mL (11.00 mM) (saturation unknown) in 10% EtOH + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear EtOH stock solution to 400 μL of PEG300 and mix evenly; then add 50 μL of Tween-80 to the above solution and mix evenly; then add 450 μL of normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 5: ≥ 2.5 mg/mL (11.00 mM) (saturation unknown) in 10% EtOH + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear EtOH stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 6: ≥ 2.5 mg/mL (11.00 mM) (saturation unknown) in 10% EtOH + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear EtOH stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)