Methods of treating disease with levoketoconazole

1. A method of treating persistent or recurrent Cushing's syndrome in a subject in need thereof, wherein the subject is being coadministered an organic cation transporter 2 (OCT2) substrate, or a pharmaceutically acceptable salt thereof, 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 due to increased exposure to the OCT2 substrate; and

if the subject experiences a dose limiting event, reducing the amount of the OCT2 substrate, or a pharmaceutically acceptable salt thereof, administered to the subject.

2. The method of claim 1 , wherein the dose limiting event is an elevated liver function test (LFT), a QTc prolongation event, abnormal kidney function, increased risk of Type B lactic acidosis, decreased fasting glucose level, anion gap acidosis, or low vitamin B-12.

3. The method of claim 1 , wherein the subject has had previous surgery or radiation to treat the subject's persistent or recurrent Cushing's syndrome.

4. The method of claim 1 , wherein the subject has not had previous surgery or radiation to treat the subject's persistent or recurrent Cushing's syndrome.

5. The method of claim 1 , wherein reducing the amount of the OCT2 substrate, or a pharmaceutically acceptable salt thereof, comprises reducing the dose of the OCT2 substrate, or a pharmaceutically acceptable salt thereof, and maintaining the frequency of administration of the OCT2 substrate, or a pharmaceutically acceptable salt thereof.

6. The method of claim 5 , wherein the dose of the OCT2 substrate, or a pharmaceutically acceptable salt thereof, is reduced by at least 25%.

7. The method of claim 5 , wherein the dose of the OCT2 substrate, or a pharmaceutically acceptable salt thereof, is reduced by at least 50%.

8. The method of claim 1 , wherein reducing the amount of the OCT2 substrate, or a pharmaceutically acceptable salt thereof, comprises maintaining the dose of the OCT2 substrate, or a pharmaceutically acceptable salt thereof, and reducing the frequency of administration of the OCT2 substrate, or a pharmaceutically acceptable salt thereof.

9. 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.

10. The method of claim 9 , wherein the first dose of the levoketoconazole, or a pharmaceutically acceptable salt thereof, is 150 mg administered twice daily.

11. 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.

12. The method of claim 1 , wherein the therapeutically effective amount of the levoketoconazole, or a pharmaceutically acceptable salt thereof, is 600 mg twice daily.

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 the OCT2 substrate, or a pharmaceutically acceptable salt thereof, may result in increased exposure to the OCT2 substrate.

14. 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 OCT2 substrate, or a pharmaceutically acceptable salt thereof, may result in one or more exposure-related adverse reactions associated with administration of the OCT2 substrate, or a pharmaceutically acceptable salt thereof.

15. The method of claim 1 , further comprising monitoring the subject for one or more exposure-related adverse reactions associated with the OCT2 substrate, or a pharmaceutically acceptable salt thereof.

16. The method of claim 15 , wherein the one or more exposure-related adverse reactions are chosen from diarrhea, nausea/vomiting, flatulence, asthenia, indigestion, abdominal discomfort, lactic acidosis, and headache.

17. The method of claim 1 , wherein the OCT2 substrate is amantadine, choline, choline salicylate, cimetidine, cisplatin, dalfampridine, dofetilide, dopamine, epinephrine, guanfacine, histamine, lamivudine, linagliptin, memantine, norepinephrine, oxaliplatin, pramipexole, ranitidine, reserpine, tipiracil, or varenicline, or a pharmaceutically acceptable salt thereof.

18. The method of claim 1 , wherein the OCT2 substrate is amantadine, amiloride, cimetidine, dopamine, famotidine, memantine, pindolol, procainamide, ranitidine, varenicline, or oxaliplatin, or a pharmaceutically acceptable salt thereof.