ENHANCED BIOAVAILABILITY OF N-(2,6-BIS(1-METHYLETHYL)PHENYL)-N'-((1-(4-(DIMETHYLAMINO)-PHENYL)CYCLOPENTYL)METHYL)UREA HYDROCHLORIDE
Methods for enhancing the bioavailability of N-(2,6-bis(1-methylethyl)phenyl)-N′-((1-(4-(dimethylamino)phenyl)cyclopentyl)-methyl)urea hydrochloride (ATR-101) through administration with food, and compositions and kits related thereto.
1 . A method of increasing the bioavailability of ATR-101 comprising orally administering to a subject in need thereof ATR-101 in unit dosage form at or near the time of oral administration of food.
2 . The method of claim 1 , wherein the ATR-101 in unit dosage form is administered at the same time or within about 30 minutes after the oral administration of food.
3 . The method of claim 1 or 2 , wherein the food is a high fat, high calorie meal.
4 . The method of any one of claims 1 to 3 , wherein the mean maximum plasma concentration (C max ) of ATR-101 in the subject in need thereof is increased when the unit dosage form of ATR-101 is administered with a meal, compared to when the unit dosage form of ATR-101 is administered under fasting conditions.
5 . The method of claim 4 , wherein C max increases by at least about 50%.
6 . The method of claim 4 , wherein C max increases by at least about 100%.
7 . The method of any one of claims 1 to 3 , wherein the area under the plasma concentration time curve (AUC 0-t ) of ATR- in the subject in need thereof is increased when the unit dosage form of ATR-101 is administered with a meal, compared to when ATR-101 is administered under fasting conditions.
8 . The method of claim 7 , wherein AUC 0-t increases by at least about 50%.
9 . The method of claim 7 , wherein AUC 0-t increases by at least about 100%.
10 . The method of any one of claims 1 to 9 , wherein the subject has a non-cancerous disorder.
11 . The method of claim 10 , wherein the subject has a non-cancerous endocrine disorder.
12 . The method of claim 10 , wherein the subject has Cushing's syndrome.
13 . The method of claim 10 , wherein the subject has congenital adrenal hyperplasia.
14 . The method of any one of claims 1 to 9 , wherein the subject has a cancerous disorder.
15 . The method of claim 14 , wherein the subject has ACC.
16 . The method of claim 14 , wherein the subject has prostate cancer.
17 . A solid pharmaceutical composition in a unit dosage form suitable for oral administration, comprising N-(2,6-bis(1-methylethyl)phenyl)-N′-((1-(4-(dimethylamino)phenyl)-cyclopentyl)methyl)urea hydrochloride (ATR-101) in combination with one or more pharmaceutically acceptable carriers or excipients, wherein ATR-101 is present in the unit dosage form at a level ranging from about 250-750 mg as measured as the free base form of ATR-101.
18 . The solid pharmaceutical composition of claim 17 , wherein ATR-101 is present in the unit dosage form at a level of about 500 mg as measured as the free base form of ATR-101.
19 . The solid pharmaceutical composition of claim 17 , wherein ATR-101 is present in the unit dosage form at a level of about 750 mg as measured as the free base form of ATR-101.
20 . The solid pharmaceutical composition of claim 17 , wherein ATR-101 is present in the unit dosage form at a level at or in excess of 50% by weight, as measured as the free base form of ATR-101, of the total weight of the unit dosage form.
21 . The solid pharmaceutical composition of claim 17 , wherein ATR-101 is present in the unit dosage form at a level at or in excess of 60% by weight, as measured as the free base form of ATR-101, of the total weight of the unit dosage form.
22 . The solid pharmaceutical composition of claim 17 , wherein ATR-101 is present in the unit dosage form at a level at or in excess of 65% by weight, as measured as the free base form of ATR-101, of the total weight of the unit dosage form.
23 . The solid pharmaceutical composition of claim 17 , wherein ATR-101 is present in the unit dosage form at a level at or in excess of 70% by weight, as measured as the free base from of ATR-101, of the total weight of the unit dosage form.
24 . The solid pharmaceutical composition of claim 17 , wherein ATR-101 has a particle size distribution as follows: d(0.1) of about 2 μm, d(0.5) of about 12 μm, and a d(0.9) of about 49 μm.
25 . The solid pharmaceutical composition of claim 17 , wherein ATR-101 has a d(0.5) particle size distribution ranging from 6 to 18 μm.
26 . The solid pharmaceutical composition of claim 17 , wherein ATR-101 has a particle size distribution ranging from 10 to 14 μm.
27 . The solid pharmaceutical composition of claim 17 , wherein ATR-101 has a particle size distribution ranging from 2 to 10 μm.
28 . The solid pharmaceutical composition of claim 17 , wherein the unit dosage form is formulated for dosing once daily.
29 . The solid pharmaceutical composition of claim 17 , wherein the unit dosage form is formulated for dosing twice daily.
30 . The solid pharmaceutical composition of claim 17 , wherein the unit dosage form is formulated for dosing three or four times daily.
31 . The solid pharmaceutical composition of claim 17 , wherein the one or more pharmaceutically acceptable carriers or excipients are selected from one or more diluents, binding agents, adhesives, disintegrants, wetting agents, lubricants, anti-adherents, glidants, and surfactants.
32 . The solid pharmaceutical composition of claim 17 in tablet form.
33 . The solid pharmaceutical composition of claim 32 , wherein the tablet is a coated tablet.
34 . A method of administering a solid pharmaceutical composition of any one of claims 17 - 33 , comprising orally administering to a subject in need thereof ATR-101 in unit dosage form.
35 . The method of administering the solid pharmaceutical composition of claim 34 , further comprising oral administration of food at or near the time of oral administration of ATR-101 in unit dosage form.
36 . The method of claim 35 , wherein the ATR-101 in unit dosage form is administered at the same time or within about 30 minutes after the food is administered.
37 . The method of claim 35 or 36 , wherein the food is a meal.
38 . The method of any one of claims 35 to 37 , wherein the mean maximum plasma concentration (C max ) of ATR-101 is increased when ATR-101 is administered with a meal, compared to when ATR-101 is administered under fasting conditions.
39 . The method of claim 38 , wherein C max increases by at least about 50%.
40 . The method of claim 38 , wherein C max increases by at least about 100%.
41 . The method of any one of claims 35 to 37 , wherein the area under the plasma concentration time curve (AUC 0-t ) of ATR-101 is increased when ATR-101 is administered with a meal, compared to when ATR-101 is administered under fasting conditions.
42 . The method of claim 41 , wherein AUC 0-t increases by at least about 50%.
43 . The method of claim 41 , wherein AUC 0-t increases by at least about 100%.
44 . The method of any one of claims 34 to 43 , wherein the subject has a non-cancerous disorder.
45 . The method of claim 44 , wherein the subject has a non-cancerous endocrine disorder.
46 . The method of claim 45 , wherein the subject has Cushing's syndrome.
47 . The method of claim 45 , wherein the subject has congenital adrenal hyperplasia.
48 . The method of any one of claims 34 to 43 , wherein the subject has a cancerous disorder.
49 . The method of claim 48 , wherein the subject has ACC.
50 . The method of claim 48 , wherein the subject has prostate cancer.
51 . A kit comprising a plurality of oral unit dosage forms of the solid pharmaceutical composition of any one of claims 17 to 33 in combination with instructions for co-administration with food at or near the time of oral administration of ATR-101 in unit dosage form.