METHODS AND COMPOSITIONS FOR THE TREATMENT OF CUSHING'S SYNDROME USING 2S, 4R KETOCONAZOLE
Methods for treating Cushing's Syndrome and other conditions associated with excessive cortisol production such as Cushing's Disease, ectopic adrenocorticotropic hormone secretion, ectopic corticotropin-releasing hormone secretion, adrenal-dependent Cushing's Syndrome, adrenal adenoma, adrenal autonomy, or any other condition associated with persistent or recurrent endogenous hypercortisolemia are provided. The methods include administration of a 2S,4R ketoconazole enantiomer substantially free of the 2R,4S enantiomer to patients according to a dosing titration schedule or at an effective amount. Treatment methods according to the invention may be safer and more effective than treatment using racemic ketoconazole.
1 . A method for treatment of Cushing's Syndrome in a patient in need thereof comprising administering a 2S,4R ketoconazole enantiomer substantially free of the 2R,4S enantiomer to the patient according to a dosing titration schedule comprising a first dosing level, said first dosing level comprising administering 150 to 300 milligrams of the 2S,4R ketoconazole enantiomer to the patient per day in 1 to 3 divided doses.
2 . The method of claim 1 wherein the first dosing level comprises administering 150 milligrams of the 2S,4R ketoconazole enantiomer to the patient two times a day.
3 . The method of claim 1 wherein the first dosing level is administered for about 8 to about 22 days.
4 . The method of claim 1 wherein the first dosing level is administered for about 15 days.
5 . The method of claim 1 further comprising measuring the patient's mean 24-hour urinary free cortisol levels, wherein a subsequent dosing level is administered if the mean 24-hour urinary free cortisol levels are greater than an upper limit of the normal range established for an assay being used at a central laboratory, and wherein the first dosing level or the subsequent dosing level is maintained if one or more of the following apply: (1) mean 24-hour urinary free cortisol levels are less than the upper limit of the normal range established for the assay being used at a central laboratory; (2) the maximum allowed dose is reached; or (3) the highest tolerated dose is reached.
6 . The method of claim 5 further comprising a second dosing level, said second dosing level comprising administering 450 milligrams of the 2S,4R ketoconazole enantiomer to the subject per day in 1 to 3 divided doses.
7 . The method of claim 6 further comprising a third dosing level, said third dosing level comprising administering 600 milligrams of the 2S,4R ketoconazole enantiomer to the subject per day in 1 to 3 divided doses.
8 . The method of claim 7 further comprising a fourth dosing level, said fourth dosing level comprising administering 750 milligrams of the 2S,4R ketoconazole enantiomer to the subject per day in 1 to 3 divided doses.
9 . The method of claim 8 further comprising a fifth dosing level, said fifth dosing level comprising administering 900 milligrams of the 2S,4R ketoconazole enantiomer to the subject per day in 1 to 3 divided doses.
10 . The method of claim 9 further comprising a sixth dosing level, said sixth dosing level comprising administering 1050 milligrams of the 2S,4R ketoconazole enantiomer to the subject per day in 1 to 3 divided doses.
11 . The method of claim 10 further comprising a seventh dosing level, said seventh dosing level comprising administering 1200 milligrams of the 2S,4R ketoconazole enantiomer to the subject per day in 1 to 3 divided doses.