Effects of Ketoconazole on the Pharmacokinetics of Mifepristone, a Competitive Glucocorticoid Receptor Antagonist, in Healthy Men

Introduction: Mifepristone, a competitive Glucocorticoid Receptor antagonist approved for Cushing syndrome, and ketoconazole, an Antifungal and steroidogenesis inhibitor, are both inhibitors of and substrates for Cytochrome P450 (CYP3A4). This study evaluated the pharmacokinetic effects of concomitant ketoconazole, a strong CYP3A4 Inhibitor, on mifepristone.

Methods: In an open-label, two-period, single-center study, healthy adult men received mifepristone 600 mg orally daily for 12 days (period 1) followed by mifepristone 600 mg daily plus ketoconazole 200 mg orally twice daily for 5 days (period 2). Serial pharmacokinetic blood samples were collected predose and over 24 h postdose on days 12 (period 1) and 17 (period 2). A cross-study comparison (using data on file) further examined whether systemic exposure to mifepristone plus ketoconazole exceeded the exposure following mifepristone 1200 mg orally administered for 7 days.

Results: Sixteen subjects were enrolled and 14 completed the study. Concomitant administration with ketoconazole increased the systemic exposure to mifepristone, based on geometric least squares mean ratios, by 28% for C _max and 38% for AUC_0-24. This increase was 85% and 87% of the exposure observed following mifepristone's highest label dose of 1200 mg/day for C _max and AUC_0-24, respectively. Adverse events (AEs) were reported in 56.3% (9/16) of subjects during administration of mifepristone alone and in 57.1% (8/14) during combination with ketoconazole. No serious AEs were reported.

Conclusion: Systemic exposure to mifepristone increased following multiple doses of mifepristone 600 mg daily plus ketoconazole 200 mg twice daily. Little to no increase in AEs occurred. Dose adjustment of mifepristone may be needed when given with ketoconazole.

Funding: Corcept Therapeutics.

CYP3A4-inhibitor; Cushing syndrome; Drug interaction; Endocrinology; Ketoconazole; Mifepristone; Pharmacokinetics.