Concomitant administration of glucocorticoid receptor modulators and cyp3a inhibitors
Abstract
Applicant provides methods of treating diseases including Cushing's syndrome and hormone-sensitive cancers by concomitant administration of a glucocorticoid receptor modulator (GRM) and steroidogenesis inhibitors, and by concomitant administration of a GRM and CYP3A inhibitors. The GRM may be, e.g., mifepristone; the CYP3A inhibitors or steroidogenesis inhibitors (collectively “inhibitors”) may be, e.g., ketoconazole or itraconazole. Inhibitors may cause toxicity or other serious adverse reactions; concomitant administration of inhibitors with other drugs may increase the risk of such toxicity and adverse reactions due to the inhibitors and/or the other drugs. Applicant has surprisingly found that GRMs may be administered to subjects receiving inhibitors without increasing the risk of adverse reactions; for example, Applicant has found that mifepristone may be concomitantly administered with ketoconazole or itraconazole, providing safe concomitant administration of the GRM and ketoconazole or itraconazole. In embodiments, the GRM dose may be reduced during concomitant administration of the GRM with inhibitors.
Claims
exact text as granted — not AI-modified1 . A method of treating hyperglycemia secondary to hypercortisolism in a patient with Cushing's syndrome, said patient taking an original once-daily (OD) dose of 1200 milligrams (mg) per day (mg/day) of mifepristone, comprising reducing said original OD mifepristone dose of 1200 milligrams mg/day to an adjusted OD mifepristone dose of 900 mg/day when the patient is receiving concomitant administration of a strong CYP3A inhibitor.
2 . The method of claim 1 , wherein said reducing comprises reducing the original OD mifepristone dose of 1200 mg/day to an adjusted OD mifepristone dose of 900 mg/day by administering a OD mifepristone dose of 600 mg/day and then administering an adjusted OD mifepristone dose of 900 mg/day when the patient is receiving concomitant administration of a strong CYP3A inhibitor.
3 . The method of claim 1 , wherein said strong CYP3A inhibitor is selected from the group consisting of ketoconazole, itraconazole, nefazodone, ritonavir, nelfinavir, indinavir, boceprevir, clarithromycin, conivaptan, lopinavir, posaconazole, saquinavir, telaprevir, cobicistat, troleandomycin, tipranivir, paritaprevir and voriconazole.
4 . The method of claim 1 , wherein said strong CYP3A inhibitor is ketoconazole.
5 . The method of claim 1 , wherein said strong CYP3A inhibitor is itraconazole.
6 . The method of claim 1 , wherein said strong CYP3A inhibitor is clarithromycin.
7 . A method of treating symptoms associated with elevated cortisol levels in a patient, said patient taking an original once-daily (OD) dose of 1200 milligrams (mg) per day (mg/day) of mifepristone, comprising reducing said original OD mifepristone dose of 1200 mg/day to an adjusted OD mifepristone dose of 900 mg/day when the patient is receiving concomitant administration of a strong CYP3A inhibitor.
8 . The method of claim 7 , wherein said reducing comprises reducing the original OD mifepristone dose of 1200 mg/day to an adjusted OD mifepristone dose of 900 mg/day by administering a OD mifepristone dose of 600 mg/day and then administering an adjusted OD mifepristone dose of 900 mg per day when the patient is receiving concomitant administration of a strong CYP3A inhibitor is ketoconazole or itraconazole.
9 . The method of claim 7 , wherein said strong CYP3A inhibitor is selected from the group consisting of ketoconazole, itraconazole, nefazodone, ritonavir, nelfinavir, indinavir, boceprevir, clarithromycin, conivaptan, lopinavir, posaconazole, saquinavir, telaprevir, cobicistat, troleandomycin, tipranivir, paritaprevir and voriconazole.
10 . The method of claim 7 , wherein said strong CYP3A inhibitor is ketoconazole.
11 . The method of claim 7 , wherein said strong CYP3A inhibitor is itraconazole.
12 . The method of claim 7 , wherein said strong CYP3A inhibitor is clarithromycin.
13 . A method of treating endogenous Cushing's syndrome in a patient, said patient taking an original once-daily (OD) mifepristone dose of 1200 milligrams (mg) per day (mg/day), comprising reducing said original OD mifepristone dose of 1200 mg/day to an adjusted OD mifepristone dose of 900 mg/day when the patient is receiving concomitant administration of a strong CYP3A inhibitor.
14 . The method of claim 13 , wherein said reducing comprises reducing the original OD mifepristone dose of 1200 mg/day to an adjusted OD mifepristone dose of 900 mg/day by administering a OD mifepristone dose of 600 mg/day and then administering an adjusted OD mifepristone dose of 900 mg/day when the patient is receiving concomitant administration of a strong CYP3A inhibitor.
15 . The method of claim 13 , wherein said strong CYP3A inhibitor is selected from the group consisting of ketoconazole, itraconazole, nefazodone, ritonavir, nelfinavir, indinavir, boceprevir, clarithromycin, conivaptan, lopinavir, posaconazole, saquinavir, telaprevir, cobicistat, troleandomycin, tipranivir, paritaprevir and voriconazole.
16 . The method of any of claims 9 to 15 claim 13 , wherein said strong CYP3A inhibitor is ketoconazole or itraconazole.
17 . The method of claim 13 , wherein said strong CYP3A inhibitor is itraconazole.
18 . The method of claim 13 , wherein said strong CYP3A inhibitor is clarithromycin.
19 - 32 . (canceled)
33 . The method of claim 1 , wherein said OD doses of mifepristone are oral OD doses of mifepristone.
34 . The method of claim 7 , wherein said OD doses of mifepristone are oral OD doses of mifepristone.
35 . The method of claim 13 , wherein said OD doses of mifepristone are oral OD doses of mifepristone.Join the waitlist — get patent alerts
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