What is the difference between metyrapone and osilodrostat (LCI699) in the treatment of Cushing's disease?

Metyrapone vs. Osilodrostat for Cushing's Disease Treatment

Osilodrostat demonstrates superior efficacy compared to metyrapone for normalizing cortisol levels in Cushing's disease, with 77-86% of patients achieving urinary free cortisol normalization versus 47-70% with metyrapone. 1, 2, 3

Mechanism of Action

Both medications inhibit cortisol synthesis but through slightly different mechanisms:

• Metyrapone: Inhibits 11β-hydroxylase (CYP11B1), blocking the conversion of 11-deoxycortisol to cortisol
• Osilodrostat: More potent inhibitor of 11β-hydroxylase and also inhibits aldosterone synthase (CYP11B2)

Efficacy Comparison

Cortisol Normalization

• Osilodrostat:

  • 77-86% of patients achieve urinary free cortisol (UFC) normalization 2, 4
  • Maintains response long-term with 81% normalization at 36 weeks 2
  • 10.5 times higher odds of complete response at 36 weeks compared to metyrapone 3

• Metyrapone:

  • 47% UFC normalization at 12 weeks in prospective studies 1
  • 70% UFC normalization at final visit in retrospective studies 5
  • Only 37% normalize late-night salivary cortisol (LNSC) 5

Speed of Action

• Both medications provide rapid cortisol reduction within hours to days 1
• Metyrapone shows 67% UFC reduction after first month of treatment 5

Side Effect Profile

Common Side Effects

• Osilodrostat:

  • Hypocortisolism (27-51% of patients) 1, 4
  • Nausea (31-42%) 1, 4
  • Headache (34%) 4
  • Fatigue (28%) 4
  • Decreased appetite (37.5%) 2
  • Arthralgia (35.4%) 2

• Metyrapone:

  • Hirsutism (common in females) 1
  • Dizziness 1
  • Arthralgia 1
  • Fatigue 1
  • Hypokalemia 1
  • Nausea 1

Hormonal Side Effects

• Osilodrostat:

  • Increased adrenal steroid precursors in 42% of patients 1
  • Hirsutism in 11% of women 1
  • Hypokalemia and hypertension due to mineralocorticoid effects 1

• Metyrapone:

  • More pronounced hyperandrogenism, particularly problematic in women 1
  • Can lead to advanced bone age in children with prolonged use 1

Regulatory Approval Status

• Osilodrostat:

  • FDA approved for Cushing's disease when surgery is not an option or has not been curative 1
  • EMA and Japan approved for treatment of endogenous Cushing's syndrome 1

• Metyrapone:

  • EMA approved for treatment of endogenous Cushing's syndrome 1
  • Off-label use in US 1

Dosing Considerations

• Osilodrostat:

  • Starting dose: 2-7 mg/day BID 1
  • Maximum dose: 30 mg BID 1
  • Requires careful titration based on cortisol levels 6

• Metyrapone:

  • Typical dose: 500 mg/day to 6 g/day in divided doses (q6-8h) 1
  • Median effective dose: 1000-1500 mg/day 1, 5

Monitoring Requirements

• Osilodrostat:

  • Monitor for hypocortisolism, especially during dose titration 1
  • Watch for hypokalemia and QTc prolongation 1
  • Monitor for hyperandrogenism in women 1

• Metyrapone:

  • Monitor for hyperandrogenism with long-term use in women 1
  • Be aware of potential cross-reactivity with 11-deoxycortisol in cortisol assays 1

Special Populations

Children and Adolescents

• Both medications should be used primarily to reduce cortisol burden while awaiting definitive surgery or radiotherapy effects 1
• Metyrapone in children: 15 mg/kg every 4h for 6 doses or 300 mg/m² every 4h 1

Pregnancy

• Metyrapone may be considered with precautions in selected pregnant women 1
• Use higher cortisol target (1.5 × ULN) in pregnancy 1

Clinical Decision Algorithm

1. For patients with mild Cushing's disease:

   • Osilodrostat preferred due to higher efficacy and FDA approval 1
   • Metyrapone as alternative if osilodrostat unavailable

2. For patients with severe hypercortisolism requiring rapid control:

   • Both medications work rapidly, but osilodrostat has higher efficacy rates 1, 3

3. For female patients concerned about hyperandrogenism:

   • Osilodrostat preferred as it causes less pronounced hyperandrogenism than metyrapone 1

4. For patients with liver concerns:

   • Both medications are options as neither requires liver function monitoring (unlike ketoconazole) 1

Pitfalls to Avoid

1. Cross-reactivity in assays: Both medications can cause cross-reactivity with 11-deoxycortisol in cortisol immunoassays, potentially leading to falsely elevated cortisol readings 1

2. Undertreatment: Insufficient dosing may be misinterpreted as treatment resistance 7

3. Overtreatment: Both medications can cause adrenal insufficiency, requiring careful dose titration 1, 7

4. Monitoring only UFC: Late-night salivary cortisol normalizes less frequently than UFC with metyrapone (37% vs 70%) 5

5. Ignoring precursor accumulation: Both medications can cause accumulation of steroid precursors leading to mineralocorticoid effects 1