Ketoconazole in Cushing's disease: is it worth a try?

Abstract

BACKGROUND:

The use of ketoconazole has been recently questioned after warnings from the European Medicine Agencies and the Food and Drug Administration due to potential hepatotoxicity. However, ketoconazole is frequently used as a drug to lower circulating cortisol levels. Several pharmacological agents have recently been approved for the treatment of Cushing's disease (CD) despite limited efficacy or significant side effects. Ketoconazole has been used worldwide for more than 30 years in CD, but in the absence of a large-scale study, its efficacy and tolerance are still under debate.

PATIENTS AND METHODS:

We conducted a French retrospective multicenter study reviewing data from patients treated by ketoconazole as a single agent for CD, with the aim of clarifying efficacy and tolerance to better determine the benefit/risk balance.

RESULTS:

Data from 200 patients were included in this study. At the last follow-up, 49.3% of patients had normal urinary free cortisol (UFC) levels, 25.6% had at least a 50% decrease, and 25.4% had unchanged UFC levels. The median final dose of ketoconazole was 600 mg/d. Forty patients (20%) received ketoconazole as a presurgical treatment; 40% to 50% of these patients showed improvement of hypertension, hypokalemia, and diabetes, and 48.7% had normal UFC before surgery. Overall, 41 patients (20.5%) stopped the treatment due to poor tolerance. Mild (<5N, inferior to 5-fold normal values) and major (>5N, superior to 5-fold normal values) increases in liver enzymes were observed in 13.5% and 2.5% of patients, respectively. No fatal hepatitis was observed.

CONCLUSIONS:

Ketoconazole is an effective drug with acceptable side effects. It should be used under close liver enzyme monitoring. Hepatotoxicity is usually mild and resolves after drug withdrawal.

• Authors: Frederic Castinetti, Laurence Guignat, Pauline Giraud, Marie Muller, Peter Kamenicky, Delphine Drui, Philippe Caron, Fiorina Luca, Bruno Donadille, Marie Christine Vantyghem, Helene Bihan, Brigitte Delemer, Gerald Raverot, Emmanuelle Motte, Melanie Philippon, Isabelle Morange, Bernard Conte-Devolx, Laurent Quinquis, Monique Martinie, Delphine Vezzosi, Maelle Le Bras, Camille Baudry, Sophie Christin-Maitre, Bernard Goichot, Philippe Chanson, Jacques Young, Olivier Chabre, Antoine Tabarin, Jerome Bertherat, Thierry Brue
• Journal: The Journal of clinical endocrinology and metabolism (J Clin Endocrinol Metab) Vol. 99 Issue 5 Pg. 1623-30 (May 2014) ISSN: 1945-7197 [Electronic] United States
• PMID: 24471573 (Publication Type: Journal Article, Multicenter Study)

Chemical References

• 14-alpha Demethylase Inhibitors
• Ketoconazole
• Hydrocortisone

Topics

• 14-alpha Demethylase Inhibitors (adverse effects, therapeutic use)
• Adolescent
• Adult
• Aged
• Aged, 80 and over
• Child
• Female
• Humans
• Hydrocortisone (urine)
• Ketoconazole (adverse effects, therapeutic use)
• Male
• Middle Aged
• Pituitary ACTH Hypersecretion (drug therapy, urine)
• Retrospective Studies
• Treatment Outcome