Isturisa

Isturisa Uses, Dosage, Side Effects, Food Interaction and all others data.

Isturisa 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.

Isturisa 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. Isturisa 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.

Isturisa 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. Isturisa is highly metabolized and requires dose adjustments in patient with hepatic dysfunction.

Trade Name Isturisa
Availability Prescription only
Generic Osilodrostat
Osilodrostat Other Names Osilodrostat
Related Drugs dexamethasone, Decadron, cyproheptadine, mifepristone
Weight 1mg, 10mg, 5mg,
Type Tablet, Oral Tablet
Formula C13H10FN3
Weight Average: 227.242
Monoisotopic: 227.085875497
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.

Groups Approved, Investigational
Therapeutic Class
Manufacturer Recordati Rare Diseases UK Ltd
Available Country United Kingdom, United States,
Last Updated: September 19, 2023 at 7:00 am
Isturisa
Isturisa

Uses

Isturisa is an oral inhibitor of cortisol synthesis used to treat Cushing's disease by normalizing hypercortisolism.

Isturisa 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.

Isturisa is also used to associated treatment for these conditions: Cushing's Disease

How Isturisa works

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.

Isturisa 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.

Toxicity

As an inhibitor of cortisol synthesis, overdose with osilodrostat may result in severe hypocortisolism. Symptoms may include nausea, vomiting, fatigue, hypotension, abdominal pain, loss of appetite, dizziness, and syncope. Treatment of overdose should include assessment of cortisol levels and supplementation with exogenous corticosteroids as necessary, as well as careful monitoring of the patient's heart rhythm, blood glucose, electrolytes, and blood pressure.

Toxicity related to its osilodrostat's mechanism of action is difficult to observe in animal test subjects as human receptor profiles and densities for osilodrostat targets differ in humans as compared to these animals - for this reason, toxicological data gleaned from animal trials is of uncertain clinical relevance in humans.

Food Interaction

  • Take with or without food. Administration with food slightly alters absorption, but not to a clinically significant extent.

Volume of Distribution

The median apparent volume of distribution of osilodrostat is 100 L.

Elimination Route

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).

Half Life

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

Clearance

Data regarding the oral clearance of osilodrostat are not currently available.

Elimination Route

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.

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