Claims for Patent: 11,278,547

Summary for Patent: 11,278,547

Title:	Methods of treating disease with levoketoconazole
Abstract:	Provided herein is a method of administering levoketoconazole, or a pharmaceutically acceptable salt thereof, to a subject in need thereof, wherein the subject is also being administered a multidrug and toxin extrusion transporter 1 (MATE1) substrate or an organic cation transporter 2 (OCT2) substrate.
Inventor(s):	Cohen; Fredric (Washington Crossing, PA)
Assignee:	Strongbridge Dublin Limited (Trevose, PA)
Application Number:	17/319,781
Patent Claims:	1. A method of treating Cushing's syndrome in a subject in need thereof, wherein the subject also has type 2 diabetes mellitus and is being co-administered metformin, or a pharmaceutically acceptable salt thereof, to improve glycemic control and wherein the subject has had previous surgery or radiation to treat the subject's Cushing syndrome, comprising: administering a therapeutically effective amount of levoketoconazole, or a pharmaceutically acceptable salt thereof, to the subject in need thereof, wherein the therapeutically effective amount of levoketoconazole, or a pharmaceutically acceptable salt thereof, is determined via a titration scheme, during the levoketoconazole titration scheme, monitoring the subject for a dose limiting event wherein the dose limiting event is a decreased fasting glucose level, abnormal kidney function, and/or a low Vitamin B-12 level; and if the subject experiences a dose limiting event, reducing the amount of metformin, or a pharmaceutically acceptable salt thereof, administered to the subject. 2. The method of claim 1, wherein the Cushing's syndrome is caused by excessive secretion of adrenocorticotrophic hormone (ACTH). 3. The method of claim 2, wherein the excessive secretion is caused by a pituitary corticotroph adenoma. 4. The method of claim 1, wherein reducing the amount of metformin, or a pharmaceutically acceptable salt thereof, comprises reducing the dose of the metformin, or a pharmaceutically acceptable salt thereof, and maintaining the frequency of administration of the metformin, or a pharmaceutically acceptable salt thereof. 5. The method of claim 4, wherein the dose of the metformin, or a pharmaceutically acceptable salt thereof, is reduced by at least 25%. 6. The method of claim 4, wherein the dose of the metformin, or a pharmaceutically acceptable salt thereof, is reduced by at least 50%. 7. The method of claim 1, wherein reducing the amount of metformin, or a pharmaceutically acceptable salt thereof, comprises maintaining the dose of the metformin, or a pharmaceutically acceptable salt thereof, and reducing the frequency of administration of the metformin, or a pharmaceutically acceptable salt thereof. 8. The method of claim 1, wherein the titration scheme comprises administering a first dose of the levoketoconazole, or a pharmaceutically acceptable salt thereof, for a first time period; increasing the dose by an amount equal to an incremental value of 150 mg daily; and determining whether the subject tolerates the increased dose; wherein the cycle is repeated so long as the subject tolerates the increased dose, wherein the incremental value at each cycle repetition is the same or different; and wherein if the subject does not tolerate the increased dose, the dose for the patient is equal to the difference between the further increased dose and the incremental value for the last cycle repetition. 9. The method of claim 8, wherein the first dose of the levoketoconazole, or a pharmaceutically acceptable salt thereof, is 150 mg administered twice daily. 10. The method of claim 1, wherein the therapeutically effective amount of the levoketoconazole, or a pharmaceutically acceptable salt thereof, is between 150 mg and 1200 mg per day. 11. The method of claim 1, wherein the therapeutically effective amount of the levoketoconazole, or a pharmaceutically acceptable salt thereof, is 600 mg twice daily. 12. The method of claim 1, further comprising informing the subject or a medical care worker that co-administration of the levoketoconazole, or a pharmaceutically acceptable salt thereof, and the metformin, or a pharmaceutically acceptable salt thereof, may result in increased exposure to metformin. 13. The method of claim 1, further comprising informing the subject or a medical care worker that co-administration of the levoketoconazole, or a pharmaceutically acceptable salt thereof, and metformin, or a pharmaceutically acceptable salt thereof, may result in one or more exposure-related adverse reactions associated with metformin, or a pharmaceutically acceptable salt thereof. 14. The method of claim 1, further comprising monitoring the subject for one or more exposure-related adverse reactions associated with metformin, or a pharmaceutically acceptable salt thereof. 15. The method of claim 14, wherein the one or more exposure-related adverse reactions are chosen from diarrhea, nausea/vomiting, flatulence, asthenia, indigestion, abdominal discomfort, lactic acidosis, and headache. 16. The method of claim 1, wherein the levoketoconazole, or a pharmaceutically acceptable salt thereof, is administered as a dosage form suitable for oral administration. 17. The method of claim 16, wherein the dosage form is an immediate release tablet. 18. The method of claim 17, wherein the tablet comprises one or more pharmaceutical excipients chosen from microcrystalline cellulose, lactose, corn starch, colloidal silicon dioxide, and magnesium stearate. 19. A method of treating Cushing's syndrome in a subject in need thereof, wherein the subject also has type 2 diabetes mellitus and is being co-administered metformin, or a pharmaceutically acceptable salt thereof, to improve glycemic control and wherein the subject has not had previous surgery or radiation to treat the subject's Cushing syndrome, comprising: administering a therapeutically effective amount of levoketoconazole, or a pharmaceutically acceptable salt thereof, to the subject in need thereof, wherein the therapeutically effective amount of levoketoconazole, or a pharmaceutically acceptable salt thereof, is determined via a titration scheme, during the levoketoconazole titration scheme, monitoring the subject for a dose limiting event wherein the dose limiting event is a decreased fasting glucose level, abnormal kidney function, and/or a low Vitamin B-12 level; and if the subject experiences a dose limiting event, reducing the amount of metformin, or a pharmaceutically acceptable salt thereof, administered to the subject. 20. The method of claim 19, wherein the Cushing's syndrome is caused by excessive secretion of adrenocorticotrophic hormone (ACTH). 21. The method of claim 20, wherein the excessive secretion is caused by a pituitary corticotroph adenoma. 22. The method of claim 19, wherein reducing the amount of metformin, or a pharmaceutically acceptable salt thereof, comprises reducing the dose of the metformin, or a pharmaceutically acceptable salt thereof, and maintaining the frequency of administration of the metformin, or a pharmaceutically acceptable salt thereof. 23. The method of claim 22, wherein the dose of the metformin, or a pharmaceutically acceptable salt thereof, is reduced by at least 25%. 24. The method of claim 22, wherein the dose of the metformin, or a pharmaceutically acceptable salt thereof, is reduced by at least 50%. 25. The method of claim 19, wherein reducing the amount of metformin, or a pharmaceutically acceptable salt thereof, comprises maintaining the dose of the metformin, or a pharmaceutically acceptable salt thereof, and reducing the frequency of administration of the metformin, or a pharmaceutically acceptable salt thereof. 26. The method of claim 19, wherein the titration scheme comprises administering a first dose of the levoketoconazole, or a pharmaceutically acceptable salt thereof, for a first time period; increasing the dose by an amount equal to an incremental value of 150 mg daily; and determining whether the subject tolerates the increased dose; wherein the cycle is repeated so long as the subject tolerates the increased dose, wherein the incremental value at each cycle repetition is the same or different; and wherein if the subject does not tolerate the increased dose, the dose for the patient is equal to the difference between the further increased dose and the incremental value for the last cycle repetition. 27. The method of claim 26, wherein the first dose of the levoketoconazole, or a pharmaceutically acceptable salt thereof, is 150 mg administered twice daily. 28. The method of claim 19, wherein the therapeutically effective amount of the levoketoconazole, or a pharmaceutically acceptable salt thereof, is between 150 mg and 1200 mg per day. 29. The method of claim 19, wherein the therapeutically effective amount of the levoketoconazole, or a pharmaceutically acceptable salt thereof, is 600 mg twice daily. 30. The method of claim 19, further comprising informing the subject or a medical care worker that co-administration of the levoketoconazole, or a pharmaceutically acceptable salt thereof, and the metformin, or a pharmaceutically acceptable salt thereof, may result in increased exposure to metformin. 31. The method of claim 19, further comprising informing the subject or a medical care worker that co-administration of the levoketoconazole, or a pharmaceutically acceptable salt thereof, and metformin, or a pharmaceutically acceptable salt thereof, may result in one or more exposure-related adverse reactions associated with metformin, or a pharmaceutically acceptable salt thereof. 32. The method of claim 19, further comprising monitoring the subject for one or more exposure-related adverse reactions associated with metformin, or a pharmaceutically acceptable salt thereof. 33. The method of claim 32, wherein the one or more exposure-related adverse reactions are chosen from diarrhea, nausea/vomiting, flatulence, asthenia, indigestion, abdominal discomfort, lactic acidosis, and headache. 34. The method of claim 19, wherein the levoketoconazole, or a pharmaceutically acceptable salt thereof, is administered as a dosage form suitable for oral administration. 35. The method of claim 34, wherein the dosage form is an immediate release tablet. 36. The method of claim 35, wherein the tablet comprises one or more pharmaceutical excipients chosen from microcrystalline cellulose, lactose, corn starch, colloidal silicon dioxide, and magnesium stearate.