Korlym May Need Dose Adjustments When Combined with Nizoral to Treat Cushing’s, Study Finds

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by Alice Melao |

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Nizoral (ketoconazole), an off-label inhibitor of steroid hormone production, can change the way the body distributes and absorbs Korlym (mifepristone), a new study finds.

Because doctors sometimes prescribe both drugs simultaneously to Cushing’s syndrome patients, they need to better understand how these drugs interact to ensure the best doses are being delivered.

The study,“Effects of Ketoconazole on the Pharmacokinetics of Mifepristone, a Competitive Glucocorticoid Receptor Antagonist, in Healthy Men,” appeared in the journal Advances in Therapy.

Cushing’s disease is characterized by excessive production of the steroid hormone cortisol. This is caused overgrowth of the pituitary gland, by benign tumors, or by medication or other tumor sources.

Surgically removing the tumor that causes hypercortisolism is usually the first therapeutic approach for Cushing’s patients. However, some patients need additional treatments to lower cortisol levels in their bodies.

Korlym blocks the activity of the glucocorticoid receptor, which indirectly regulates the actions of cortisol. In 2012, the U.S. Food and Drug Administration (FDA) approved it to treat Cushing’s patients who had not responded to surgery or were not eligible for surgical treatment.

The body quickly absorbs Korlym, which is metabolized by cytochrome P450 (CYP), an enzyme that deconstructs the medicine into three  active compounds.

Nizoral is approved by the FDA as an antifungal medicine. Given its potential to inhibit steroid production, it is sometimes used off-label to treat Cushing’s. However, Nizoral strongly inhibits the CYP enzyme, suggesting it could affect the clearance of Korlym in Cushing’s patients.

To address this, Dat Nguyen, director of medical communications at Corcept Therapeutics, studied 14 healthy men who received Korlym (600 mg) daily for 12 days, followed by five days of Korlym plus Nizoral (200 mg twice daily). Blood samples were collected before and after treatment.

Results showed that Nizoral increased the blood concentration of Korlym by 28 percent. It also increased exposure to one of Korlym’s active metabolites by 70 percent. The clinical effects of this metabolite are not fully clear. But its lower affinity to the glucocorticoid receptor, compared to Korlym and the other active metabolites, minimize its clinical importance.

Nevertheless, Nizoral did not change Korlym’s clinical effects, as shown by decreased cortisol and ACTH (adrenocorticotropic hormone) blood levels achieved both with Korlym alone and the combo therapy.

In addition, increased exposure to Korlym did not exceed the maximum tolerable dose (1200 mg), researchers found. However, the team believes that Korlym migh need dose adjustments when used in combination with Nizoral.

“Additional studies may be needed to determine if longer durations of concomitant administration and/or using mifepristone [Korlym] doses beyond 600 mg will produce exposure within the acceptable ranges,” researchers wrote.

Adverse effects reported during the study were mainly mild to moderate in severity, and consistent with the known safety profiles of the two medicines. The rates of treatment-related adverse events were similar with both regimens.