What is the recommended treatment approach for a patient with Cushing's disease, particularly for those who are not candidates for surgery or have failed surgical treatment, using Isturisa (osilodrostat)?

Isturisa (Osilodrostat) for Cushing's Disease

Isturisa (osilodrostat) is FDA-approved for adult patients with Cushing's disease when pituitary surgery is not an option or has failed to achieve cure, and should be initiated at 2 mg orally twice daily with careful titration based on cortisol response and tolerability. 1

Primary Indication and Patient Selection

Osilodrostat is specifically indicated for adult patients with Cushing's disease in two clinical scenarios 1:

• Patients who are not surgical candidates due to medical comorbidities, tumor location, or patient refusal
• Patients with persistent or recurrent hypercortisolism after failed pituitary surgery

Important caveat: In pediatric and adolescent patients, osilodrostat should only be used short-term to normalize cortisol levels in preparation for surgery or while awaiting radiotherapy response—not as long-term therapy—due to effects on growth and pubertal development 2.

Mechanism and Efficacy

Osilodrostat inhibits 11β-hydroxylase (CYP11B1), blocking the final step of cortisol synthesis 2. This mechanism provides:

• Rapid onset of action (within hours), making it suitable when urgent cortisol normalization is needed 2
• High rates of biochemical control with urinary free cortisol (UFC) normalization in the majority of treated patients 3, 4
• Sustained cortisol reduction with improvements in weight, blood pressure, glucose metabolism, and quality of life 4, 5

Dosing Protocol

Initial Dosing

Start at 2 mg orally twice daily (with or without food) in adults with normal hepatic function 1. For hepatic impairment:

• Child-Pugh B: Start at 1 mg twice daily 1
• Child-Pugh C: Start at 1 mg once daily in the evening 1

Titration Strategy

• Increase by 1-2 mg twice daily no more frequently than every 2 weeks based on cortisol response, tolerability, and clinical improvement 1
• Maximum recommended dose is 30 mg twice daily 1
• Critical pitfall: There is no correlation between pre-treatment hypercortisolism severity and the dose required for control—titration must be individualized based on response, not predicted 6

Monitoring During Titration

Monitor UFC levels and clinical parameters (weight, blood pressure, glucose, symptoms) to guide dose adjustments 5. The twice-daily dosing schedule is more convenient than metyrapone's frequent dosing and achieves high normalization rates 2.

Pre-Treatment Requirements

Before initiating osilodrostat, you must 1:

• Correct hypokalemia and hypomagnesemia (osilodrostat increases adrenal precursors including 11-deoxycorticosterone, which has mineralocorticoid activity)
• Obtain baseline electrocardiogram to assess QTc interval
• Review all concomitant medications for potential drug interactions

Critical Monitoring and Safety

Hypocortisolism and Adrenal Insufficiency

• Most common adverse effect (incidence >20%) 1
• Monitor closely for signs: fatigue, weakness, hypotension, nausea, hypoglycemia 5
• Dose reduction or temporary interruption may be necessary 1
• Post-surgical pitfall: After TNS surgery in patients on osilodrostat, initial biochemical assessment may be equivocal despite clinical hypoadrenalism—HPA axis function may take 2+ months to normalize 6

QTc Prolongation

• Perform ECG at baseline and periodically during treatment 1
• Use with caution in patients with risk factors: congenital long QT syndrome, heart failure, bradyarrhythmias, electrolyte abnormalities, or concomitant QT-prolonging medications 1, 5

Elevations in Adrenal Precursors and Androgens

Monitor for and manage 2, 1:

• Hypokalemia (from mineralocorticoid excess)
• Worsening hypertension and edema
• Hirsutism and acne in females (from androgen accumulation)
• Hypogonadism in males (though less common than with ketoconazole) 2

Tumor Growth Surveillance

• Critical concern: Blocking cortisol synthesis removes negative feedback, potentially allowing ACTH-secreting tumors to grow 2, 6
• Obtain MRI 6-12 months after initiating treatment, then every few years 2
• Monitor ACTH levels—progressive elevations may signal tumor growth requiring imaging 2
• If progressive tumor growth occurs, suspend medical treatment and reassess management plan 2

Drug Interactions

CYP3A4 Inhibitors

Reduce osilodrostat dose by half when used with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, ritonavir) 1

CYP3A4 and CYP2B6 Inducers

• May require increased osilodrostat dosing when used with strong inducers (e.g., rifampin, phenytoin, carbamazepine) 1
• Conversely, may need dose reduction if inducers are discontinued 1

Clinical Scenarios for Use

Osilodrostat is appropriate in multiple treatment phases 4:

• Preoperative treatment: To normalize cortisol before surgery in severe cases with life-threatening metabolic, psychiatric, infectious, or cardiovascular/thromboembolic complications 2
• Primary medical therapy: When surgery is contraindicated, refused, or not available
• Second-line treatment: After failed pituitary surgery with persistent or recurrent disease
• Bridging therapy: After second surgery or while awaiting radiotherapy effects (which may take months to years)

Advantages Over Other Steroidogenesis Inhibitors

Compared to alternatives 2:

• Faster and more convenient than metyrapone (twice daily vs. every 4 hours)
• No hepatotoxicity risk unlike ketoconazole (which requires weekly liver function monitoring)
• No hypogonadism in men unlike ketoconazole
• High normalization rates with sustained efficacy

Special Populations

Pregnancy and Lactation

• No data support use in pregnancy 1
• Breastfeeding is not recommended during treatment and for at least one week after discontinuation 1

Pediatric Use

Osilodrostat is currently being evaluated in a phase II trial in children and adolescents (NCT03708900), but should only be used short-term to prepare for definitive treatment, not as long-term therapy 2.

Ectopic and Adrenal Cushing Syndrome

While FDA approval and most data focus on Cushing's disease, emerging evidence supports osilodrostat use in ectopic ACTH syndrome and adrenal Cushing syndrome 7. Management should account for disease severity, comorbidities, and performance status, with individualized starting doses and titration frequency 7.