Concomitant administration of glucocorticoid receptor modulators and CYP3A inhibitors
Applicant provides methods of treating diseases including Cushing's syndrome and hormone-sensitive cancers by concomitant administration of a glucocorticoid receptor antagonist (GRA) and steroidogenesis inhibitors, and by concomitant administration of a GRA and CYP3A inhibitors. Applicant provides methods of treating diseases including Cushing's syndrome and hormone-sensitive cancers by concomitant administration of mifepristone and ketoconazole. Subjects treated with CYP3A inhibitors or steroidogenesis inhibitors may suffer from toxicity or other serious adverse reactions; concomitant administration of other drugs would be expected to increase the risk of such toxicity and adverse reactions. Applicant has surprisingly found that GRAs may be administered to subjects receiving CYP3A inhibitors or steroidogenesis inhibitors such as ketoconazole without increasing risk adverse reactions; for example, Applicant has found that mifepristone may be concomitantly administered with ketoconazole (a CYP3A inhibitor and a steroidogenesis inhibitor), providing safe concomitant administration of the GRA and ketoconazole. In embodiments, the GRA dose may be reduced.
1. A method of controlling hyperglycemia secondary to hypercortisolism in a patient with endogenous Cushing's syndrome, said patient taking an original once-daily dose of 1200 mg per day of mifepristone, the method comprising the steps of:
reducing the original once-daily dose to an adjusted once-daily dose of 900 milligrams (mg) per day of mifepristone, and
administering the adjusted once-daily dose of 900 mg per day of mifepristone and a strong CYP3A inhibitor to the patient,
wherein said strong CYP3A inhibitor is selected from the group consisting of ketoconazole, itraconazole, nefazodone, ritonavir, nelfinavir, boceprevir, clarithromycin, conivaptan, lopinavir, saquinavir, telaprevir, cobicistat, troleandomycin, tipranivir, and paritaprevir.
2. The method of claim 1 , wherein said strong CYP3A inhibitor is selected from the group consisting of nefazodone, ritonavir, nelfinavir, boceprevir, clarithromycin, conivaptan, lopinavir, saquinavir, telaprevir, cobicistat, troleandomycin, tipranivir, and paritaprevir.
3. The method of claim 1 , wherein said CYP3A inhibitor is ketoconazole.
4. The method of claim 2 , wherein said CYP3A inhibitor is clarithromycin.
5. The method of claim 1 , wherein said CYP3A inhibitor is itraconazole.
6. A method of controlling hyperglycemia secondary to hypercortisolism in a patient with endogenous Cushing's syndrome, said patient taking a strong CYP3A inhibitor selected from ketoconazole, itraconazole, nefazodone, ritonavir, nelfinavir, indinavir, boceprevir, clarithromycin, conivaptan, lopinavir, posaconazole, saquinavir, telaprevir, cobicistat, troleandomycin, tipranivir, paritaprevir and voriconazole, the method comprising administering to the patient a once-daily dose of mifepristone of 900 milligrams (mg) per day.
7. The method of claim 6 , wherein said CYP3A inhibitor is ketoconazole.
8. The method of claim 6 , wherein said CYP3A inhibitor is troleandomycin.
9. The method of claim 6 , wherein said CYP3A inhibitor is itraconazole.
10. The method of claim 6 , wherein said CYP3A inhibitor is clarithromycin.
11. The method of claim 6 , wherein said CYP3A inhibitor is lopinavir, ritonavir, or both.
12. The method of claim 6 , wherein said CYP3A inhibitor is nelfinavir.
13. The method of claim 6 , wherein said CYP3A inhibitor is cobicistat.
14. The method of claim 6 , wherein said CYP3A inhibitor is nefazodone.