What treatment options are available for a patient with Cushing's Disease who has undergone surgery but continues to experience hypercortisolism, and how can Isturisa (Osilodrostat) be used in this scenario?

Isturisa (Osilodrostat) for Cushing's Disease After Surgery: Practical Facts

Primary Indication and FDA Approval

Isturisa (osilodrostat) is FDA-approved specifically for adult patients with Cushing's disease when pituitary surgery is not an option or has not been curative. 1 This makes it an ideal choice for persistent or recurrent hypercortisolism following transsphenoidal surgery.

Dosing and Titration Protocol

Initial Dosing

• Start at 2 mg orally twice daily (with or without food) in patients with normal hepatic function 1
• For Child-Pugh B hepatic impairment: reduce starting dose to 1 mg twice daily 1
• For Child-Pugh C hepatic impairment: reduce starting dose to 1 mg once daily in the evening 1

Dose Titration Strategy

• Increase by 1-2 mg twice daily, no more frequently than every 2 weeks based on urinary free cortisol (UFC) levels, tolerability, and clinical improvement 1
• Maximum recommended dose is 30 mg twice daily 1
• The twice-daily dosing makes it advantageous for patients who struggle with more complex medication regimens 2

Critical Pre-Treatment Requirements

• Correct hypokalemia and hypomagnesemia before initiating therapy 1
• Obtain baseline electrocardiogram (ECG) to assess QTc interval 1

Mechanism and Efficacy

How It Works

Osilodrostat is a potent oral inhibitor of 11β-hydroxylase (CYP11B1) and aldosterone synthase, blocking cortisol synthesis at the adrenal level 3, 2

Clinical Trial Results

• In the pivotal LINC 3 trial, 86% of patients maintained normal UFC on osilodrostat versus 29% on placebo (p<0.0001) 3, 4
• In LINC 4 trial, 77% of patients achieved UFC normalization at 12 weeks versus 8% on placebo (p<0.0001), with 81% maintaining response at 36 weeks 5
• At week 24 of open-label treatment, 53% of patients achieved complete response without dose escalation 4
• Rapid onset of action with sustained cortisol reduction throughout treatment 4

Clinical Improvements Beyond Cortisol Control

Patients demonstrate significant improvements in:

• Body weight reduction 3
• Blood pressure normalization 3
• Total and LDL cholesterol reduction 3
• Fasting glucose and HbA1c improvement 3
• Quality of life and depression scores 3

Adverse Effects and Management

Most Common Side Effects (>20% incidence)

• Adrenal insufficiency (28-51%) - most common during initial dose titration 1, 4
• Fatigue (28%) 1
• Nausea (31-42%) 1, 4, 5
• Headache (34%) 1, 4
• Edema 1

Effects from Elevated Adrenal Precursors (42% of patients)

• Hypokalemia - requires monitoring and correction 3, 1
• Worsening hypertension 3
• Edema 3
• Hirsutism (11% of women) 3
• Acne 2

Serious Adverse Events

• QTc prolongation - requires baseline and periodic ECG monitoring 1
• Hypocortisolism requiring dose reduction or glucocorticoid replacement (36% needed replacement in LINC 3) 3

Critical Monitoring Requirements

Laboratory Monitoring

• 24-hour urinary free cortisol (UFC) - primary endpoint for dose titration 4, 5
• Serum potassium and magnesium levels - monitor for hypokalemia 1
• Morning cortisol levels - assess for hypocortisolism 3
• Liver function tests 1

Cardiac Monitoring

• ECG at baseline and periodically during treatment to assess QTc interval 1
• Use with caution in patients with risk factors for QTc prolongation 1

ACTH Monitoring Caveat

• Progressive ACTH elevation may occur during treatment, potentially leading to pituitary adenoma enlargement 6
• Consider pituitary MRI surveillance, especially if planning subsequent radiotherapy 6

Drug Interactions

CYP3A4 Strong Inhibitors

• Reduce osilodrostat dose by half when used concomitantly with strong CYP3A4 inhibitors 1

CYP3A4 and CYP2B6 Inducers

• May require osilodrostat dose increase when used with strong inducers 1
• May require dose reduction if inducers are discontinued during osilodrostat therapy 1

Clinical Use Scenarios

Post-Surgical Persistent Disease

Osilodrostat achieves fast and effective biochemical and clinical response in patients with residual adenoma after non-curative surgery 6

Bridge to Radiotherapy

Can be used to control hypercortisolism while awaiting the delayed effects of pituitary radiotherapy 3

Surgery Refusal or Contraindication

Effective as primary medical therapy when surgery is not feasible, with ability to achieve disease control prior to eventual surgery if patient changes decision 6

Important Clinical Pitfalls

No Dose-Response Correlation

There is no correlation between pre-treatment hypercortisolism severity and the osilodrostat dose required for control - requires individualized titration based on response 6

Post-Surgical Assessment Confusion

In patients who undergo surgery after osilodrostat treatment, post-operative biochemical assessment may be equivocal despite clinical hypoadrenalism, as the drug's effects can confound interpretation of surgical cure 6

Hypoadrenalism Management

• Most hypocortisolism events occur during the initial dose-titration period 3
• Manageable with dose reductions, interruptions, or temporary glucocorticoid replacement 3
• Requires close clinical monitoring and patient education on adrenal crisis symptoms 1

Comparison to Alternative Medical Therapies

Advantages Over Ketoconazole and Metyrapone

• More potent cortisol reduction with 77-86% achieving UFC normalization versus 64% with ketoconazole and 71% with metyrapone 3, 5
• Simpler twice-daily dosing versus every 4-6 hours for metyrapone 3
• No hepatotoxicity monitoring required unlike ketoconazole 3
• Lower rates of hyperandrogenism compared to metyrapone 3

When to Consider Bilateral Adrenalectomy Instead

Reserve bilateral adrenalectomy for severe refractory disease or life-threatening complications (such as left ventricular hypertrophy with cirrhosis), as it provides immediate definitive control but requires lifelong hormone replacement and carries risk of Nelson syndrome 7

Pediatric Considerations

Osilodrostat is NOT currently approved for pediatric use - effects and safety are being evaluated in a phase II trial (NCT03708900) 3 In children and adolescents, medical therapies like metyrapone and ketoconazole should be confined to pre-surgical cortisol normalization or bridging to radiotherapy effect, not long-term management 3