Concomitant administration of glucocorticoid receptor modulators and CYP3A inhibitors

• US 10,195,214 B2
• Filed: 06/19/2017
• Issued: 02/05/2019
• Est. Priority Date: 03/01/2017
• Status: Active Grant

• Current Assignee: Corcept Therapeutics Inc.
• Original Assignee: Corcept Therapeutics Inc.
• Inventors: Belanoff, Joseph K.
• Primary Examiner(s): Lundgren, Jeffrey S
• Assistant Examiner(s): Simmons, Chris E
• Application Number:
  US15/627,359
• Publication Number:
  US 20170326157A1
• Time in Patent Office: 596 Days
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/567 substituted in position 17 alpha, e.g. mestranol, norethandrolone
• CPC Class Codes: A61K 31/575 substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
• CPC Class Codes: A61K 31/7048 having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin , digitoxin or digoxin
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/0056 Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/46 for decreasing, blocking or antagonising the activity of glucocorticosteroids

Abstract

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.

Claims

1. A method of treating Cushing'"'"'s syndrome in a patient who is taking an original once-daily dose of 1200 mg or 900 mg per day of mifepristone, comprising the steps of:

reducing the original once-daily dose to an adjusted once-daily dose of 600 mg mifepristone,

administering the adjusted once-daily dose of 600 mg 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, nelfmavir, indinavir, boceprevir, clarithromycin, conivaptan, lopinavir, posaconazole, saquinavir, telaprevir, cobicistat, troleandomycin, tipranivir, paritaprevir and voriconazole.

2. The method of claim 1, wherein said CYP3A inhibitor is ketoconazole.

3. The method of claim 1, wherein said CYP3A inhibitor is itraconazole.

4. The method of claim 1, wherein said CYP3A inhibitor is clarithromycin.

5. A method of treating symptoms associated with elevated cortisol levels in a patient who is taking an original once-daily dose of 1200 mg or 900 mg per day of mifepristone, comprising the steps of:

reducing the original once-daily dose to an adjusted once-daily dose of 600 mg mifepristone,

administering the adjusted once-daily dose of 600 mg 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, nelfmavir, indinavir, boceprevir, clarithromycin, conivaptan, lopinavir, posaconazole, saquinavir, telaprevir, cobicistat, troleandomycin, tipranivir, paritaprevir and voriconazole.

6. The method of claim 5, wherein said CYP3A inhibitor is itraconazole.

7. The method of claim 5, wherein said CYP3A inhibitor is ketoconazole.

8. The method of claim 5, wherein said CYP3A inhibitor is clarithromycin.

9. The method of claim 5, wherein said CYP3A inhibitor is itraconazole.

10. A method of controlling hyperglycemia secondary to hypercortisolism in a patient with endogenous Cushing'"'"'s syndrome who is taking an original once-daily dose of 1200 mg or 900 mg per day of mifepristone, comprising the steps of:

reducing the original once-daily dose to an adjusted once-daily dose of 600 mg mifepristone,

administering the adjusted once-daily dose of 600 mg 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, nelfmavir, indinavir, boceprevir, clarithromycin, conivaptan, lopinavir, posaconazole, saquinavir, telaprevir, cobicistat, troleandomycin, tipranivir, paritaprevir and voriconazole.

11. The method of claim 10, wherein said CYP3A inhibitor is ketoconazole.

12. The method of claim 10, wherein said CYP3A inhibitor is itraconazole.

13. The method of claim 10, wherein said CYP3A inhibitor is clarithromycin.