Osilodrostat API Manufacturers

General Description:

Osilodrostat, identified by CAS number 928134-65-0, is a notable compound with significant therapeutic applications. 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.

Indications:

This drug is primarily indicated for: 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. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Osilodrostat undergoes metabolic processing primarily in: 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. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Osilodrostat are crucial for its therapeutic efficacy: The oral absorption of osilodrostat is rapid, with a T_max of approximately 1 hour, and assumed to be essentially complete. Exposure (i.e. AUC and C_max) 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). The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Osilodrostat is an important consideration for its dosing schedule: The elimination half-life of osilodrostat is approximately 4 hours. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Osilodrostat exhibits a strong affinity for binding with plasma proteins: 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. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Osilodrostat from the body primarily occurs through: 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. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Osilodrostat is distributed throughout the body with a volume of distribution of: The median apparent volume of distribution of osilodrostat is 100 L. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Osilodrostat is a critical factor in determining its safe and effective dosage: Data regarding the oral clearance of osilodrostat are not currently available. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Osilodrostat exerts its therapeutic effects through: Osilodrostat lowers endogenous cortisol levels by inhibiting the enzyme that catalyzes the final step in cortisol synthesis. As endogenous cortisol levels function as a surrogate marker for drug effect, 24-hour urine free cortisol levels should be assessed 1-2x weekly during the initial titration stage and every 1-2 months thereafter to ensure cortisol levels remain physiologically appropriate. Osilodrostat is highly metabolized and requires dose adjustments in patient with hepatic dysfunction. Osilodrostat can cause a dose-dependent prolongation of the QTc interval and should be used with caution in patients with a higher baseline risk (e.g. concomitant QTc-prolonging medications, electrolyte abnormalities). Prior to beginning therapy, patients should have a baseline ECG and any electrolyte abnormalities (especially hypokalemia and/or hypomagnesemia) should be remedied. As osilodrostat halts cortisol synthesis at its final stage, its use can result in the accumulation of cortisol precursors, aldosterone precursors, and androgens. The accumulation of the cortisol precursor 11-deoxycorticosterone can activate mineralocorticoid receptors which may lead to hypokalemia, edema, or hypertension. Patients should be monitored for these symptoms as they are evidence of elevated 11-deoxycorticosterone levels, and for symptoms such as hirustism, acne, and hypertrichosis which may be suggestive of excessive circulating androgen levels. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Osilodrostat functions by: 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. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Osilodrostat belongs to the class of organic compounds known as benzonitriles. These are organic compounds containing a benzene bearing a nitrile substituent, classified under the direct parent group Benzonitriles. This compound is a part of the Organic compounds, falling under the Benzenoids superclass, and categorized within the Benzene and substituted derivatives class, specifically within the Benzonitriles subclass.

Categories:

Osilodrostat is categorized under the following therapeutic classes: Antiadrenal Preparations, Anticorticosteroids, Cortisol Synthesis Inhibitors, Cytochrome P-450 CYP11B2, antagonists & inhibitors, Cytochrome P-450 CYP1A2 Inhibitors, Cytochrome P-450 CYP1A2 Inhibitors (moderate), Cytochrome P-450 CYP2B6 Substrates, Cytochrome P-450 CYP2C19 Inhibitors, Cytochrome P-450 CYP2C19 Inhibitors (weak), Cytochrome P-450 CYP2D6 Inhibitors, Cytochrome P-450 CYP2D6 Inhibitors (weak), Cytochrome P-450 CYP2D6 Substrates, Cytochrome P-450 CYP2E1 Inhibitors, Cytochrome P-450 CYP2E1 Inhibitors (strength unknown), Cytochrome P-450 CYP3A Inhibitors, Cytochrome P-450 CYP3A Substrates, Cytochrome P-450 CYP3A4 Inhibitors, Cytochrome P-450 CYP3A4 Inhibitors (weak), Cytochrome P-450 CYP3A4 Substrates, Cytochrome P-450 CYP3A5 Inhibitors, Cytochrome P-450 CYP3A5 Inhibitors (weak), Cytochrome P-450 Enzyme Inhibitors, Cytochrome P-450 Substrates, Cytochrome P450 11B1 Inhibitors, MATE 1 Inhibitors, MATE inhibitors, OAT1/SLC22A6 inhibitors, OAT3/SLC22A8 Inhibitors, OATP1B1/SLCO1B1 Inhibitors, OCT1 inhibitors, OCT2 Inhibitors, Systemic Hormonal Preparations, Excl. Sex Hormones and Insulins, UGT1A4 substrates, UGT2B7 substrates. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.