Pharmaceutical compositions, dosage forms and methods for oral administration of epothilones

Abstract

The invention relates to methods of increasing the bioavailability of orally administered epothilones. Epothilones administered by the methods of the invention are sufficiently bioavailable to have a pharmacological effect. The invention further relates to pharmaceutical compositions, pharmaceutical dosage forms, and kits for use in the methods of the invention.

1. A method of increasing the bioavailability of orally administered epothilones  comprising orally administering to a human one or more epothilones  compounds of Formula: 
                 
 
       wherein:
 G is selected from the group consisting of  alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo, 
                 
 
 W is O or NR 16 ;  
 X is O; S; CHR 17 ; or H, R 18 ;  
 Y is selected from the group consisting of  O; H, H; H, OR 22 ; OR 23 , OR 23 ; NOR 24 ; H, NOR 25   NHOR 25 ; H, HNR 26 R 27   NR 26   R   27 ; NHNR 28 R 29 ;  H, NHNR 30 R 31  or CHR 32 , where OR 23 , OR 23  can be a cyclic ketal;  
 B 1  and B 2  are selected from the group consisting of  independently H, OR 33 , OCOR 34 , OCONR 35 R 36 , NR 37 R 38 , or NR 39 CONR 40 R 41 ;  
 D is selected from the group consisting of  NR 42 R 43  or heterocyclo;  
 R 1 , R 2 , R 3 , R 4 , and R 5  are selected from  independently H,  or lower alkyl;  
 R 8 , R 9 , R 10  and R 11  are selected from the group consisting of  independently H, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, heterocyclo or substituted heterocyclo;  
 R 17 , R 18 , R 22 , and R 23  are selected from the group consisting of  independently H, alkyl, and  or substituted alkyl;  
 R 24 , R 25 , R 26 , R 28 ,  R 30 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 39 , R 40 , R 41 , R 42 , R 51 , R 52 , and R 53 , and R 61    are selected from the group of  independently H, alkyl, substituted alkyl, aryl or substituted aryl;  
 R 12 , R 16 , R 27 , R 29 ,  R 31 , R 38 , and R 43 ,  are selected from the group consisting of  independently H, alkyl, substituted alkyl, substituted aryl, cycloalkyl, heterocyclo, R 51 C═O, R 52 OC═O, R 53 SO 2 , hydroxy, and  O-alkyl or O-substituted alkyl, ; 
 or a pharmaceutically acceptable salt,  solvate, clathrate, hydrate or prodrug thereof, and orally administering one or more pharmaceutically acceptable acid neutralizing buffers, wherein the bioavailability of the compound is increased with the acid neutralizing buffer compared to that without the acid neutralizing buffer.  
 
     
     
       2. The method of claim  1    17 , wherein the pharmaceutically acceptable acid neutralizing buffer is administered concurrently with the epothilone  compound. 
     
     
       3. The method of claim  1    17 , wherein the pharmaceutically acceptable acid neutralizing buffer is administered before the epothilone  compound. 
     
     
       4. The method of  claim 3 , wherein the pharmaceutically acceptable acid neutralizing buffer is administered not more than about 1 hour before the epothilone  compound. 
     
     
       5. The method of claim  1    17 , wherein the pharmaceutically acceptable acid neutralizing buffer is administered after the epothilone  compound. 
     
     
       6. The method of  claim 5 , wherein the pharmaceutically acceptable acid neutralizing buffer is administered not more than about 1 hour after the epothilone  compound. 
     
     
       7. The method of claim  1    17 , wherein the pharmaceutically acceptable acid neutralizing buffer is administered before and after the epothilone  compound. 
     
     
       8. The method of  claim 7 , wherein the pharmaceutically acceptable acid neutralizing buffer is administered not more than about 1 hour before and not more than about 1 hour after the epothilone  compound is administered. 
     
     
       9. The method of claim  1    17 , wherein the pharmaceutically acceptable acid neutralizing buffer is administered in an amount sufficient to deliver at least about 20 milliequivalents of acid neutralization capacity. 
     
     
       10. The method of claim  1    17 , wherein the pharmaceutically acceptable acid neutralizing buffer is administered as an aqueous solution having a pH of between about 5 to 9. 
     
     
       11. The method of claim  1    17 , wherein the pharmaceutically acceptable acid neutralizing buffer is administered as an aqueous solution comprising anhydrous dibasic sodium phosphate, sodium citrate dihydrate, and anhydrous citric acid. 
     
     
       12. The method of  claim 11 , wherein the pH of the aqueous solution is about 7. 
     
     
       13. The method of claim  1    17 , wherein the bioavailability of the one or more epothilones  compound or a pharmaceutically acceptable salt,  solvate, clathrate, hydrate, or prodrug thereof is at least about 20 percent. 
     
     
       14. The method of claim  1    17 , wherein the one or more epothilones  compound or a pharmaceutically acceptable salt,  solvate, clathrate, hydrate, or prodrug thereof is orally administered as a solution in propylene glycol and ethanol, wherein the in  ratio of propylene glycol:ethanol is about 80:20. 
     
     
       15. The method of claim  1    17 , wherein the one or more epothilones  compound or a pharmaceutically acceptable salt,  solvate, clathrate, hydrate, or prodrug thereof is administered in a total amount of about 0.05 to about 200 mg/kg/day. 
     
     
       16. The method of  claim 15 , wherein the one or more epothilones of  compound or a pharmaceutically acceptable salt,  solvate, clathrate, hydrate, or prodrug thereof is administered in about 2 to 4 divided doses. 
     
     
       17. The method of  claim 1 , wherein the epothilone is [1S-[1R*,3R*(E),7R*,10S*,11R*,16S*]]-7,11-dihydroxy 8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl-17-oxa-4-azabicyclo[14.1.0]heptadecane-5,9-dione.  The method of  claim 1 , wherein the compound is 
                 
 
       or a pharmaceutically acceptable solvate, clathrate, hydrate, or prodrug thereof. 
     
     
       18. The method of  claim 1  comprising:
 (a) orally administering an aqueous solution of a pharmaceutically acceptable acid neutralizing buffer comprising anhydrous dibasic sodium phosphate, sodium citrate dihydrate, and anhydrous citric acid;  
 (b) orally administering the one or more epothilones  compounds or a pharmaceutically acceptable salt,  solvate, clathrate, hydrate, or prodrug thereof as a solution of propylene glycol; and  
 (c) orally administering an aqueous solution of a pharmaceutically acceptable acid neutralizing buffer comprising anhydrous dibasic sodium phosphate, sodium citrate dihydrate, and anhydrous citric acid.  
 
     
     
       19. The method of  claim 18 , wherein the epothilone is [1S-[1R*,3R*(E),7R*,10S*,11R*,16S*]]-7,11-dihydroxy 8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl-17-oxa-4-azabicyclo[14.1.0]heptadecane-5,9-dione.  The method of  claim 18 , wherein the compound is 
                 
 
       or a pharmaceutically acceptable solvate, clathrate, hydrate, or prodrug thereof. 
     
     
       20. A kit for use in a method of increasing the bioavailability of orally administered epothilones which comprises  comprising:
 (i) a first component comprising one or more epothilones of Formula: 
                 
 G is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo, 
                 
 
 W is O or NR 16 ;  
 X is O; S; CHR 17 ; or H, R 18    
 Y is selected from the group consisting of O; H, H; H, OR 22 ; OR 23 , OR 23 ; NOR 24 ; H, NOR 25 ; H, HNR 26 R 27 ; NHNR 28 R 29 ; H, NHNR 30 R 31  or CHR 32 , where OR 23 , OR 23  can be a cyclic ketal;  
 B 1  and B 2  are selected from the group consisting of H, OR 33 , OCOR 34 , OCONR 35 R 36 , NR 37 R 38 , or NR 39 CONR 40 R 41    
 D is selected from the group consisting of NR 42 R 43  or heterocyclo;  
 R 1 , R 2 , R 3 , R 4 , and R 5  are selected from H, lower alkyl;  
 R 8 , R 9 , R 10  and R 11  are selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, heterocyclo or substituted heterocyclo;  
 R 17 , R 18 , R 22 , and R 23  are selected from the group consisting of H, alkyl, and substituted alkyl;  
 R 24 , R 25 , R 26 , R 28 , R 30 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 39 , R 40 , R 41 , R 42 , R 51 , R 52 , R 53 , and R 61  are selected from the group of H, alkyl, substituted alkyl, aryl or substituted aryl;  
 R 12 , R 16 , R 27 , R 29 , R 31 , R 38 , and R 43 , are selected from the group consisting of H, alkyl, substituted alkyl, substituted aryl, cycloalkyl, heterocyclo, R 51 C═O, R 52 OC═O, R 53 SO 2 , hydroxy, and O-alkyl or O-substituted alkyl;  a compound of formula 
                 
 
 
 or a pharmaceutically acceptable salt,  solvate, clathrate, hydrate, or prodrug thereof; and  
 (ii) a second component comprising a pharmaceutically acceptable acid neutralizing buffer,  
 wherein the first component and the second component are provided as an oral dosage form or as a pharmaceutical composition that can be reconstituted with a solvent to provide a liquid oral dosage.  
 
     
     
       21. The kit of  claim 20 , wherein at least one of the first component or the second component is provided as a solid oral dosage form. 
     
     
       22. The kit of  claim 21 , wherein at least one of the first component or the second component is anhydrous. 
     
     
       23. The kit of  claim 20 , wherein at least one of the first component or the second component is provided as a pharmaceutical composition that can be reconstituted with a solvent to provide a liquid oral dosage form. 
     
     
       24. The kit of  claim 23 , wherein at least one of the first component or the second component is provided as a tablet. 
     
     
       25. The kit of  claim 23 , wherein at least one of the first component or the second component is anhydrous. 
     
     
       26. The kit of  claim 23 , further comprising solvents for reconstituting the first or second components. 
     
     
       27. The kit of  claim 26 , wherein the solvent for reconstituting the first component is a mixture of propylene glycol and ethanol. 
     
     
       28. A pharmaceutical composition suitable for oral administration to a mammal comprising:
 (i) one or more epothilones  compounds of Formula: 
                 
 wherein:  
 G is selected from the group consisting of  alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo, 
                 
 
 W is O or NR 16   NR 16 ;  
 X is O; S; CHR 17 ; or H, R 18 ;  
 Y is selected from the group consisting of  O; H, H; H, OR 22 ; OR 23 , OR 23 ; NOR 24 ; H, NOR 25   NHOR 25 ; H, HNR 26 R 27   NR 26   R   27 ; NHNR 28 R 29 ;  H, NHNR 30 R 31  or CHR 32 , where OR 23 , OR 23  can be a cyclic ketal;  
 B 1  and B 2  are selected from the group consisting of  independently H, OR 33 , OCOR 34 , OCONR 35 R 36 , NR 37 R 38 , or NR 39 CONR 40 R 41    
 D is selected from the group consisting of  NR 42 R 43  or heterocyclo;  
 R 1 , R 2 , R 3 , R 4 , and R 5  are selected from  independently H,  or lower alkyl;  
 R 8 , R 9 , R 10  and R 11  are selected from the group consisting of  independently H, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, heterocyclo or substituted heterocyclo;  
 R 17 , R 18 , R 22 , and R 23  are selected from the group consisting of  independently H, alkyl, and  or substituted alkyl;  
 R 24 , R 25 , R 26 , R 28 ,  R 30 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 39 , R 40 , R 41 , R 42 , R 51 , R 52 , and R 53 , and R 61    are selected from the group of  independently H, alkyl, substituted alkyl, aryl or substituted aryl;  
 R 12 , R 16 , R 27 , R 29 ,  R 31 , R 38 , and R 43 ,  are selected from the group consisting of  independently H, alkyl, substituted alkyl, substituted aryl, cycloalkyl, heterocyclo, R 51 C═O, R 52 OC═O, R 53 SO 2 , hydroxy, and  O-alkyl or O-substituted alkyl;  
 
 or a pharmaceutically acceptable salt,  solvate, clathrate, hydrate, or prodrug thereof, in solid form; and  
 (ii) a solid pharmaceutically acceptable acid neutralizing buffer in an amount sufficient to reduce decomposition of the one or more epothilones  compounds, or a pharmaceutically acceptable salt,  solvate, clathrate, hydrate, or prodrug thereof when the pharmaceutical composition is reconstituted with a solvent to provide a liquid oral dosage form.  
 
     
     
       29. The pharmaceutical composition of claim  28    33 , wherein the pharmaceutically acceptable acid neutralizing buffer provides a liquid oral dosage form having a pH between about 5 to 9. 
     
     
       30. The pharmaceutical composition of claim  28    33 , wherein the pharmaceutically acceptable acid neutralizing buffer is present in an amount sufficient to provide at least about 20 milliequivalents of acid neutralization capacity. 
     
     
       31. The pharmaceutical composition of claim  28    33 , wherein the pharmaceutically acceptable acid neutralizing buffer is a dibasic phosphate-citric acid-citrate buffer. 
     
     
       32. The pharmaceutical composition of claim  28    33 , wherein the one or more epothilones  compound or a pharmaceutically acceptable salt,  solvate, clathrate, hydrate, or prodrug thereof is present in an amount of between about 0.05 and 200 mg. 
     
     
       33. The pharmaceutical composition of  claim 28 , wherein the epothilone is [1S-[1R*,3R*(E),7R*,10S*,11R*,16S*]]-7,11-dihydroxy 8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl-17-oxa-4-azabicyclo[14.1.0]heptadecane-5,9-dione.  The pharmaceutical composition of  claim 28 , wherein the compound is 
                 
 
       or a pharmaceutically acceptable solvate, clathrate, hydrate, or prodrug thereof. 
     
     
       34. A kit comprising the pharmaceutical composition of claim  28    33  and a solvent for reconstituting the pharmaceutical composition to provide an oral dosage form. 
     
     
       35. The kit of  claim 34 , wherein the solvent comprises propylene glycol, ethanol, and phosphate buffer (1M, pH 8). 
     
     
       36. The kit of  claim 35 , wherein the ratio of propylene glycol:ethanol:phosphate buffer is about 58:12:30. 
     
     
       37. A liquid oral dosage form suitable for oral administration to a mammal comprising:
 (i) one or more epothilones  compounds of Formula: 
                 
 wherein:  
 G is selected from the group consisting of  alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo, 
                 
 
 W is O or NR 16 ;  
 X is O; S; CHR 17 ; or H, R 18 ;  
 Y is selected from the group consisting of  O; H, H; H, OR 22 ; OR 23 ,  OR23   OR 23 ; NOR 24 ; H, NOR 25   NHOR 25 ; H, HNR 26 R 27   NR 26   R   27 ; NHNR 28 R 29 ;   H, NHNR 30 R 31  or CHR 32 , where OR 23 , OR 23  can be a cyclic ketal;  
 B 1  and B 2  are selected from the group consisting of  independently H, OR 33 , OCOR 34 , OCONR 35 R 36 , NR 37 R 38 , or NR 39 CONR 40 R 41    
 D is selected from the group consisting of  NR 42 R 43  or heterocyclo;  
 R 1 , R 2 , R 3 , R 4 , and R 5  are selected from  independently H,  or lower alkyl;  
 R8, R9, R10 and R 11  R   8   , R   9   , R   10    and R   11  are selected from the group consisting ofindependently H, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, heterocyclo or substituted heterocyclo;  
 R 17 , R 18 , R 22 , and R 23  are selected from the group consisting of  independently H, alkyl, and  or substituted alkyl;  
 R 24 , R 25 , R 26 , R 28 ,  R 30 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 39 , R 40 , R 41 , R 42 , R 51 , R 52 , and R 53 , and R 61    are selected from the group of  independently H, alkyl, substituted alkyl, aryl or substituted aryl;  
 R 12 , R 16 , R 27 , R 29 ,  R 31 , R 38 , and R 43 ,  are selected from the group consisting of  independently H, alkyl, substituted alkyl, substituted aryl, cycloalkyl, heterocyclo, R 51 C═O, R 52 OC═O, R 53 SO 2 , hydroxy, and  O-alkyl or O-substituted alkyl, ; 
 
 or a pharmaceutically acceptable salt,  solvate, clathrate, hydrate, or prodrug thereof; and  
 (ii) a pharmaceutically acceptable liquid carrier.  
 
     
     
       38. The liquid oral dosage form of  claim 37 , wherein the epothilone is [1S-[1R*,3R*(E),7R*,10S*,11R*,16S*]]-7,11-dihydroxy 8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl-17-oxa-4-azabicyclo[14.1.0]heptadecane-5,9-dione.  The liquid oral dosage form of  claim 37 , wherein the compound is 
                 
 
       
         or a pharmaceutically acceptable solvate, clathrate, hydrate, or prodrug thereof. 
       
     
     
       39. The liquid oral dosage form of claim  37    38 , further comprising a pharmaceutically acceptable acid neutralizing buffer in an amount sufficient to reduce decomposition of the one or more epothilones  compound, or a pharmaceutically acceptable salt,  solvate, clathrate, hydrate, or prodrug thereof compared to a pharmaceutical composition without the buffer. 
     
     
       40. The liquid oral dosage form of  claim 39 , wherein the pH of the liquid oral dosage form is between about 5 to 9. 
     
     
       41. The liquid oral dosage form of  claim 39 , wherein the buffer is present in an amount sufficient to provide at least about 20 milliequivalents of acid neutralization capacity. 
     
     
       42. The liquid oral dosage form of claim  37    38 , wherein the solvent is propylene glycol, ethanol, and water buffered with a phosphate buffer at pH about 8. 
     
     
       43. The liquid oral dosage form of  claim 42 , wherein the propylene glycol, ethanol, and water buffered with a phosphate buffer are present in a ratio of about 58:12:30. 
     
     
       44. The liquid oral dosage form of  claim 42 , wherein the epothilone is [1S-[1R*,3R*(E),7R*,10S*,11R*,16S*]]-7,11-dihydroxy 8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl-17-oxa-4-azabicyclo[14.1.0]heptadecane-5,9-dione.  The dispersible buffered tablet of  claim 48  wherein the compound is 
                 
 
       
         or a pharmaceutically acceptable solvate, clathrate, hydrate, or prodrug thereof. 
       
     
     
       45. The liquid oral dosage form of claim  37    38 , wherein the one or more epothilones  compound or a pharmaceutically acceptable salt,  solvate, clathrate, hydrate, or prodrug thereof is present in an amount of between about  0 . 05  and 200 mg. 
     
     
       46. The liquid oral dosage form of  claim 39 , wherein the buffer is dibasic phosphate-citric acid-citrate buffer. 
     
     
       47. An article of manufacture which comprises:
 (a) a sealable container suitable to carry a liquid or solid pharmaceutical;  
 (b) one or more epothilones  a compound of formula 
                 
 
 
       or a pharmaceutically acceptable salt,  solvate, clathrate, hydrate or prodrug thereof; and
 (c) a pharmaceutically acceptable carrier suitable to deliver the epothilone  compound orally.  
 
     
     
       48. A dispersible buffered tablet which comprises:
 (i) one or more epothilones  compounds of Formula: 
                 
 wherein:  
 G is selected from the group consisting of  alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo, 
                 
 
 W is O or NR 16 ;  
 X is O; S; CHR 17 ; or H, R 18 ;  
 Y is selected from the group consisting of  O; H, H; H, OR 22 ; OR 23 ,  OR23   OR 23 ; NOR 24 ; H, NOR 25   NHOR 25 ; H, HNR 26 R 27   NR 26   R   27 ; NHNR 28 R 29 ;  H, NHNR 30 R 31  or CHR 32 , where OR 23 , OR 23  can be a cyclic ketal;  
 B 1  and B 2  are selected from the group consisting of  independently H, OR 33 , OCOR 34 , OCONR 35 R 36 , NR 37 R 38 , or NR 39 CONR 40 R 41    
 D is selected from the group consisting of  NR 42 R 43  or heterocyclo;  
 R 1 , R 2 , R 3 , R 4 , and R 5  are selected from  independently H,  or lower alkyl;  
 R 8 , R 9 , R 10  and R 11  are selected from the group consisting of  independently H, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, heterocyclo or substituted heterocyclo;  
 R 17 , R 18 , R 22 , and R 23  are selected from the group consisting of  independently H, alkyl, and  or substituted alkyl;  
 R 24 , R 25 , R 26 , R 28 ,  R 30 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 39 , R 40 , R 41 , R 42 , R 51 , R 52 , and R 53 , and R 61    are selected from the group of  independently H, alkyl, substituted alkyl, aryl or substituted aryl;  
 R 12 , R 16 , R 27 , R 29 ,  R 31 , R 38 , and R 43 ,  are selected from the group consisting of  independently H, alkyl, substituted alkyl, substituted aryl, cycloalkyl, heterocyclo, R 51 C═O  R 51   C═O , R 52 OC═O, R 53 SO 2  R   53   SO   2 , hydroxy, and  O-alkyl or O-substituted alkyl,  ; 
 
 or a pharmaceutically acceptable salt,  solvate, clathrate, hydrate, or prodrug thereof; and  
 (ii) buffer components which are suitable to neutralize gastric fluids for a time sufficient to allow said epothilone  compound to be absorbed.  
 
     
     
       49. The kit of  claim 20 , wherein the first and second component is provided as a liquid oral dosage form. 
     
     
       50. The kit of  claim 49 , wherein the one or more epothilones  compound or a pharmaceutically acceptable salt,  solvate, clathrate, hydrate, or prodrug thereof is present in an amount of between about 0.05 and 200 mg and the pharmaceutically acceptable acid neutralizing buffer is present in an amount sufficient to provide at least about 20 milliequivalents of acid neutralization capacity. 
     
     
       51. The kit of  claim 20 , wherein the first component and the second component is provided as a pharmaceutical composition that can be reconstituted with a solvent to provide a liquid oral dosage form; the one or more epothilones  compound or a pharmaceutically acceptable salt,  solvate, clathrate, hydrate, or prodrug thereof is present as a in an amount of between about  0 . 05  and  200  mg; and the pharmaceutically acceptable acid neutralization buffer is present in an amount sufficient to provide at least about  20  milliequivalents of acid neutralization capacity. 
     
     
       52. The kit of  claim 20 , wherein the epothilone is [ 1 S-[ 1 R*,3R*(E), 7 R*, 10 S*, 11 R*, 16 S*]]- 7 , 11 -dihydroxy  8 , 8 , 10 , 12 , 16 -pentamethyl- 3 -[ 1 -methyl- 2 -( 2 -methyl- 4 -thiazolyl)ethenyl- 17 -oxa- 4 -azabicyclo[ 14 . 1 . 0 ]heptadecane- 5 , 9 -dione and the pharmaceutically acceptable acid neutralizing buffer comprises dibasic sodium phosphate, sodium citrate, and anhydrous citric acid.  The kit of  claim 20 , wherein the pharmaceutically acceptable acid neutralizing buffer comprises dibasic sodium phosphate, sodium citrate, and anhydrous citric acid. 
     
     
       53. A method for the treatment of any one of breast cancer, lung cancer, pancreatic cancer and/or prostate cancer in a human, comprising administering to said human a therapeutically effective amount of a compound of formula                    
       and ketoconazole. 
     
     
       54. A method of treating any one of breast cancer, lung cancer, pancreatic cancer and/or prostate cancer in a human comprising administering to the human a therapeutically-effective combination of ( 1 ) an amount of ketoconazole and ( 2 ) an amount of a Compound ( 1 ) of formula                    
       or a pharmaceutically-acceptable solvate, clathrate, hydrate, or prodrug thereof, wherein the administration will provide an anticancer effect for a greater period of time than the effect obtainable with the amount of the Compound ( 1 ) alone.