What is an alternative treatment for adrenal steroidogenesis inhibition with a different adverse profile?

Osilodrostat and Metyrapone: Alternative Steroidogenesis Inhibitors with Distinct Adverse Profiles

If seeking an alternative to ketoconazole for adrenal steroidogenesis inhibition, osilodrostat and metyrapone offer different adverse effect profiles—osilodrostat avoids hepatotoxicity and male hypogonadism but causes hyperandrogenism in women and hypokalemia, while metyrapone similarly avoids liver toxicity and male hypogonadism but also causes hyperandrogenism and hypokalemia. 1

Key Distinguishing Features by Drug

Osilodrostat

Osilodrostat represents the most effective alternative with FDA approval specifically for Cushing's disease, demonstrating 86% UFC normalization in Phase 3 trials. 1

Unique advantages:

• No hepatotoxicity monitoring required (unlike ketoconazole which requires regular LFT monitoring) 1
• No male hypogonadism (avoiding the gynecomastia and testosterone suppression seen with ketoconazole) 1
• Twice-daily dosing improves compliance compared to ketoconazole's 2-3 times daily schedule 1, 2
• Rapid onset of action within hours 1

Distinct adverse effects:

• Increased androgenic precursors causing hirsutism and acne in women (requires careful monitoring for hyperandrogenism) 1, 3
• Increased mineralocorticoid precursors causing hypertension and hypokalemia 1, 3
• QTc prolongation risk 1, 3
• Cross-reaction with 11-deoxycortisol in routine cortisol assays 1

Dosing: Start 2 mg twice daily, titrate by 1-2 mg every 2 weeks, maximum 30 mg twice daily 3

Metyrapone

Metyrapone provides rapid cortisol control within hours with approximately 70% UFC normalization, avoiding both hepatotoxicity and male hypogonadism. 1

Unique advantages:

• No hepatotoxicity (no LFT monitoring required unlike ketoconazole) 1
• No male hypogonadism (preferred in men over ketoconazole) 1
• Rapid onset of action within hours 1
• EMA approved for Cushing's syndrome 1

Distinct adverse effects:

• Increased androgenic precursors causing hirsutism in women (requires monitoring for hyperandrogenism with long-term use) 1, 4
• Increased mineralocorticoid precursors causing hypertension and hypokalemia 1, 4
• Possible cross-reactivity with 11-deoxycortisol in cortisol immunoassays 1
• More frequent dosing required (every 6-8 hours) 1

Dosing: 500 mg/day to 6 g/day divided every 6-8 hours 1, 4

Clinical Decision Algorithm

Choose Osilodrostat when:

• Long-term treatment is anticipated (expected to be increasingly used given high efficacy) 1
• Patient compliance with multiple daily doses is poor (twice-daily dosing advantage) 1, 2
• Male patient (avoids hypogonadism) 1
• Patient has liver disease or elevated LFTs (no hepatotoxicity) 1
• Avoid in women with concerns about hirsutism/acne or patients with severe hypokalemia 1

Choose Metyrapone when:

• Male patient (avoids hypogonadism) 1
• Patient has liver disease or elevated LFTs (no hepatotoxicity) 1
• Severe hypercortisolism requiring rapid control 1
• Short-term treatment anticipated 5
• Avoid in patients with severe or uncontrolled hypokalemia 1, 5

Choose Ketoconazole when:

• Female patient (testosterone decrease is beneficial) 1
• Young woman desiring pregnancy 1
• Patient without severe liver disease 1, 5
• Ease of dose titration is priority 1

Critical Monitoring Requirements

For both osilodrostat and metyrapone:

• Monitor for adrenal insufficiency with regular UFC measurements every 1-2 weeks during titration 1, 3
• Check electrolytes regularly for hypokalemia 1, 3
• Obtain baseline and follow-up ECGs for QTc prolongation 1, 3
• In women, monitor closely for hyperandrogenism (hirsutism, acne) 1
• Monitor blood pressure for hypertension from mineralocorticoid excess 1

Common Pitfalls to Avoid

Cross-reactivity with cortisol assays: Both osilodrostat and metyrapone cause accumulation of 11-deoxycortisol, which can cross-react in routine cortisol immunoassays, potentially falsely elevating cortisol measurements 1

Underestimating hypokalemia risk: The mineralocorticoid precursor accumulation can cause significant hypokalemia requiring potassium supplementation and/or mineralocorticoid receptor antagonists 1

Inadequate monitoring for adrenal insufficiency: UFC is not useful for diagnosing adrenal insufficiency; morning cortisol or LNSC should be used 1

Gender-specific considerations: While both drugs avoid male hypogonadism (a ketoconazole problem), they cause hyperandrogenism in women, requiring careful patient selection and monitoring 1