Introduction
Korlym (mifepristone) is a prescription medication approved by the FDA for the treatment of hyperglycemia in adults with endogenous Cushing's syndrome who have type 2 diabetes mellitus or glucose intolerance and are not candidates for surgery or have not responded to surgery. It is a glucocorticoid receptor antagonist that represents a significant advancement in the medical management of Cushing's syndrome.
Mechanism of Action
Korlym competitively blocks the glucocorticoid receptor (GR) type II. Mifepristone has high affinity for the GR, approximately 10 times that of dexamethasone and 4 times that of cortisol. By blocking cortisol binding at the receptor level, it reduces the effects of excess cortisol characteristic of Cushing's syndrome. Mifepristone also has antiprogestin activity and binds to the progesterone receptor with higher affinity than progesterone itself.
Indications
- Treatment of hyperglycemia secondary to hypercortisolism in adult patients with endogenous Cushing's syndrome who have type 2 diabetes mellitus or glucose intolerance
- Patients must have failed surgery or not be candidates for surgery
Dosage and Administration
- Initial dose: 300 mg orally once daily
- Dose titration: May be increased in increments of 300 mg based on clinical response and tolerability
- Maximum dose: 1200 mg once daily (or 20 mg/kg per day in patients <60 kg)
- Administration: Take with a meal to enhance absorption
- Special populations:
- Renal impairment: No dosage adjustment necessary - Hepatic impairment: Use with caution; not studied in severe hepatic impairment - Elderly: No specific dosage adjustment recommended
Pharmacokinetics
- Absorption: Absolute bioavailability approximately 69%; high-fat meal increases AUC by 25-39%
- Distribution: Volume of distribution approximately 2.8 L/kg; 98% protein bound (primarily to alpha-1 acid glycoprotein)
- Metabolism: Primarily hepatic via CYP3A4; active metabolites: monodemethylated, didemethylated, and hydroxylated derivatives
- Elimination: Primarily fecal (83%) with minor renal excretion (9%); terminal half-life approximately 85 hours
Contraindications
- Pregnancy (may terminate pregnancy)
- Women with Cushing's syndrome who are pregnant or wish to become pregnant
- Patients taking simvastatin, lovastatin, or CYP3A4 substrates with narrow therapeutic indices
- Patients with known hypersensitivity to mifepristone or any product components
- Patients requiring chronic corticosteroid therapy
Warnings and Precautions
- Pregnancy risk: Korlym may terminate pregnancy; women of reproductive potential must use effective contraception
- Hypokalemia: May occur; monitor potassium levels at baseline and weekly during initiation and titration
- Adrenal insufficiency: Possible due to glucocorticoid receptor blockade
- Vaginal bleeding: May occur in women; monitor and evaluate if persistent
- QTc prolongation: Dose-dependent QTc prolongation observed; monitor in patients with heart conditions
- CYP3A4 interactions: Strong inhibitor of CYP3A4; significant drug interaction potential
Drug Interactions
- Strong CYP3A4 inhibitors: May increase mifepristone exposure (avoid concomitant use)
- CYP3A4 substrates: May increase concentrations of drugs metabolized by CYP3A4 (avoid narrow therapeutic index drugs)
- Corticosteroids: Mifepristone may reduce effectiveness of systemic corticosteroids
- QTc-prolonging drugs: Additive effects possible
- Simvastatin and lovastatin: Contraindicated due to increased risk of myopathy
Adverse Effects
- Most common (>20%): Nausea, fatigue, headache, decreased blood potassium, arthralgia, vomiting, peripheral edema, hypertension, dizziness, worsening hypertension, anemia
- Serious adverse effects: Adrenal insufficiency, severe hypokalemia, vaginal bleeding, QT prolongation, hepatic transaminase elevations
- Other notable effects: Endometrial hypertrophy, thyroid dysfunction, rash, insomnia
Monitoring Parameters
- Baseline and weekly: Serum potassium (especially during dose titration)
- Regular monitoring: Blood glucose, clinical signs of adrenal insufficiency
- Periodic monitoring: Liver function tests, ECG (particularly in patients with cardiac risk factors)
- Women: Monitor for vaginal bleeding and endometrial changes
- Clinical assessment: Blood pressure, signs of edema, mood changes
- Therapeutic response: Improvement in hyperglycemia, weight, and other Cushing's symptoms
Patient Education
- Take Korlym exactly as prescribed, preferably with a meal
- Report any signs of hypokalemia (muscle weakness, cramps, palpitations)
- Women of childbearing potential must use effective non-hormonal contraception
- Report any unusual vaginal bleeding or menstrual changes
- Inform all healthcare providers about Korlym use due to significant interaction potential
- Do not take any new medications without consulting your healthcare provider
- Regular blood tests are necessary to monitor safety and effectiveness
- Report any signs of adrenal insufficiency (fatigue, weakness, nausea, dizziness)
- Keep all follow-up appointments for monitoring
References
1. FDA. Korlym (mifepristone) prescribing information. 2023. 2. Fleseriu M, et al. Mifepristone, a glucocorticoid receptor antagonist, produces clinical and metabolic benefits in patients with Cushing's syndrome. J Clin Endocrinol Metab. 2012;97(6):2039-2049. 3. Castinetti F, et al. Mifepristone for Cushing's syndrome: a systematic review and meta-analysis. Lancet Diabetes Endocrinol. 2022;10(5):320-331. 4. Nieman LK, et al. Treatment of Cushing's syndrome: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2015;100(8):2807-2831. 5. ClinicalTrials.gov. Study of the safety and efficacy of mifepristone for the treatment of endogenous Cushing's syndrome (SEISMIC). NCT00569582.