What is the role of osilodrostat in treating Cushing's disease?

Osilodrostat in Cushing's Disease Treatment

Osilodrostat is a highly effective FDA-approved medication for Cushing's disease with 86% UFC normalization rate, and should be used as first-line medical therapy in patients for whom pituitary surgery is not an option or has not been curative. 1

Mechanism of Action and Efficacy

Osilodrostat is a potent cortisol synthesis inhibitor that works by inhibiting 11beta-hydroxylase (CYP11B1), the enzyme responsible for the final step of cortisol biosynthesis in the adrenal gland 2. This mechanism results in:

• Rapid decrease in urinary free cortisol (UFC) levels
• Sustained reduction in cortisol levels
• 86% UFC normalization rate in clinical trials 1
• Improvement in clinical signs of hypercortisolism 3

Dosing and Administration

• Starting dose: 2 mg twice daily (orally) 1, 2
• Dose titration: Adjust every 1-2 weeks based on UFC levels and tolerability
• Maintenance dose: Typically 2-7 mg twice daily (maximum 30 mg twice daily) 1
• Can be taken with or without food 2
• Half-life: Approximately 4 hours 2

Clinical Indications

Osilodrostat is FDA-approved for:

• Patients with Cushing's disease in whom pituitary surgery is not an option
• Patients with persistent or recurrent Cushing's disease after failed pituitary surgery 1, 4

Monitoring Parameters

• UFC levels (primary efficacy marker)
• Morning serum cortisol
• Late-night salivary cortisol
• Serum potassium levels
• Testosterone levels (especially in women)
• ECG for QTc interval
• Liver function tests
• Blood pressure

Adverse Effects

Common adverse effects include:

• Adrenal insufficiency (28.6%) 5
• Nausea (42%) 3
• Headache (34%) 3
• Fatigue (28%) 3
• Hypokalemia (requiring potassium supplementation or mineralocorticoid antagonist therapy) 2
• Increased androgenic and mineralocorticoid precursors 1
  • In women: hirsutism (12%) and acne (11%) 2
• QTc prolongation (dose-dependent) 2

Drug Interactions

• Strong CYP3A4 inhibitors: Reduce osilodrostat dose by half 2
• Strong CYP3A4 and CYP2B6 inducers: May decrease osilodrostat efficacy, requiring dose adjustments 2
• Use caution with CYP1A2 and CYP2C19 substrates with narrow therapeutic indices 2

Special Populations

• Hepatic impairment: No dose adjustment needed for mild impairment (Child-Pugh A); dose adjustment required for moderate (Child-Pugh B) and severe impairment (Child-Pugh C) 2
• Renal impairment: No dosage adjustment required, but UFC levels should be interpreted with caution in moderate to severe renal impairment 2
• Pregnancy: No available data on use in pregnant women; animal studies showed no adverse effects at clinically relevant doses 2
• Breastfeeding: Not recommended during treatment and for one week after the final dose 2
• Pediatric patients: Safety and effectiveness not established 2
• Geriatric patients: No dosage adjustment required based on age 2

Advantages Over Other Medical Therapies

Compared to other medical therapies for Cushing's disease, osilodrostat offers:

• Higher efficacy (86% UFC normalization) compared to ketoconazole (65%), pasireotide (15-26%), and cabergoline (40%) 1
• Rapid onset of action with cortisol reduction within hours 6
• Twice-daily dosing, making it suitable for patients who have difficulty adhering to more complex regimens 4
• FDA approval specifically for Cushing's disease 1

Clinical Pearls and Pitfalls

• Hypocortisolism: Monitor for signs of adrenal insufficiency (nausea, vomiting, fatigue, low blood pressure, abdominal pain, dizziness, syncope) 2
• Electrolyte imbalance: Regular monitoring of potassium levels is essential 1
• QTc prolongation: Perform baseline ECG and monitor periodically, especially when increasing doses 2
• Hyperandrogenism: Women should be monitored for signs of hirsutism and acne 1
• Laboratory interference: Osilodrostat may cross-react with 11-deoxycortisol in cortisol immunoassays 1
• Dose titration: Slower up-titration may minimize adverse effects 7

In real-world clinical practice, osilodrostat has demonstrated effectiveness across various doses (2-20 mg/day), with 70% of patients achieving UFC normalization 5. Its potent and rapid action makes it an important addition to the therapeutic arsenal for managing Cushing's disease, particularly when surgical options have been exhausted.