Methods for administering dpd inhibitors in combination with 5-fu and 5-fu prodrugs

Abstract

Methods for improved administration and dosing of DPD inhibitors in combination with 5-FU and/or 5-FU prodrugs are provided, comprising first administering to a patient in need thereof a DPD inhibitor that substantially eliminates activity of the enzyme and thereafter administering 5-FU or a 5-FU prodrug, wherein the level of 5-FU or 5-FU prodrug is in substantial excess of DPD inhibitor in the patient.

1 . A method for treating cancer in a patient comprising first administering a DPD inhibitor and thereafter administering 5-FU or a 5-FU prodrug, wherein the DPD inhibitor is administered at a dose between 2.5-5 mg/m 2 , and at least about four hours thereafter administering 5-FU or a 5-FU prodrug, wherein the 5-FU or 5-FU prodrug is administered at a dose such that at its time of administration the 5-FU or 5-FU prodrug is present in the patient in excess of the DPD inhibitor. 
     
     
         2 . (canceled) 
     
     
         3 . The method of  claim 1 , wherein the 5-FU or 5-FU prodrug is administered at least about 12 hours after the DPD inhibitor is administered. 
     
     
         4 . (canceled) 
     
     
         5 . The method of  claim 1 , wherein the 5-FU or 5-FU prodrug is administered at a time when at least 1-4 elimination half-lives for the DPD inhibitor have passed since the DPD inhibitor was administered. 
     
     
         6 . (canceled) 
     
     
         7 . The method of  claim 1 , wherein the 5-FU or 5-FU prodrug is administered at a dose such that at its time of administration the 5-FU or 5-FU prodrug is present in the patient in at least 2-fold excess, at least 3-fold excess, or at least 5-fold excess of the DPD inhibitor. 
     
     
         8 . (canceled) 
     
     
         9 . The method of  claim 1 , wherein the DPD inhibitor is an irreversible DPD inhibitor. 
     
     
         10 . (canceled) 
     
     
         11 . The method of  claim 1 , wherein the 5-FU or 5-FU prodrug is selected from the group and their 5′-esters, including phosphate esters: consisting of 5-fluorouridine, 5-fluorocytidine, 5-fluoro-2-deoxyuridine, 5-fluoro-2-deoxycytidine, 5′-deoxy-4′,5-fluorouridine, and 5-fluoro arabinosyluracil. 5′-Deoxy-5-fluorouridine, 1-(2-tetrahydrofuranyl)-5-fluorouracil, 1-C 1-8  alkylcarbamoyl-5-fluorouracil derivative, 1-(2-tetrahydrofuryl)-5-fluorouracil, 5′-deoxy-5-fluoro-N-[(pentyloxy)carbonyl]-cytidine (capecitabine), or a compound that is converted to 5-FU in vivo. 
     
     
         12 . The method of  claim 1 , wherein the 5-FU or 5-FU prodrug is 5-FU or capecitabine. 
     
     
         13 . The method of  claim 1 , wherein the DPD inhibitor is eniluracil or a prodrug thereof. 
     
     
         14 . The method of  claim 1 , wherein the DPD inhibitor is eniluracil and the 5-FU or 5-FU prodrug is 5-FU or capecitabine. 
     
     
         15 - 18 . (canceled) 
     
     
         19 . The method of  claim 1 , wherein the DPD inhibitor is eniluracil, the 5-FU or 5-FU prodrug is 5-FU, the eniluracil is administered at a dose between about 2.5-5 mg/m 2 , and the 5-FU is administered at a dose between about 0.5-80 mg/m 2  or between about 0.5-40 mg/m 2 . 
     
     
         20 . The method of  claim 1 , wherein the DPD inhibitor comprises a 5-substituted uracil compound or a prodrug thereof. 
     
     
         21 . (canceled) 
     
     
         22 . The method of  claim 1 , wherein the DPD inhibitor comprises a uracil compound selected from the group consisting of eniluracil, 5-propynyluracil, 5-cyanouracil, 5-propynyluracil, 5-bromoethynyluracil, 5-(1-chlorovinyl)uracil, 5-iodouracil, 5-bromovinyluracil, (E)-5-(2-bromovinyl)uracil 5-hex-1-ynyluracil, 5-vinyluracil, 5-trifluorouracil, 5-bromouracil and 5-(2-bromo-l-chlorovinyl)uracil. 
     
     
         23 . (canceled) 
     
     
         24 . A method for treating cancer in a patient comprising first administering eniluracil at a dose between 2.5-5 mg/m 2  and thereafter administering 5-FU at least about 4 hours after the eniluracil is administered, wherein the 5-FU is administered at a dose such that at its time of administration the 5-FU is present in the patient in excess of the DPD inhibitor. 
     
     
         25 . (canceled) 
     
     
         26 . The method of  claim 24 , wherein the 5-FU is administered at least about 12 hours after the eniluracil is administered. 
     
     
         27 . The method of  claim 24 , wherein the 5-FU is administered when at least about 1-4 elimination half-lives for eniluracil have passed since the eniluracil was administered. 
     
     
         28 . (canceled) 
     
     
         29 . The method of  claim 24 , wherein the 5-FU is administered at a dose such that at its time of administration the 5-FU is present in the patient in at least 2-fold excess, at least 3-fold excess, or at least 5-fold excess of the DPD inhibitor. 
     
     
         30 . (canceled) 
     
     
         31 . (canceled) 
     
     
         32 . The method of  claim 24 , wherein the 5-FU is administered at a dose between about 0.5-40 mg/m 2 . 
     
     
         33 - 42 . (canceled) 
     
     
         43 . A method for treating cancer in a patient comprising first administering eniluracil and thereafter administering capecitabine, wherein the eniluracil is administered at a dose between about 2.5-5 mg/m 2 , and wherein the 5-FU is administered after at least 1-4 elimination half-lives for eniluracil have passed since the eniluracil was administered. 
     
     
         44 . The method of  claim 43 , wherein the capecitabine is administered at least about 4 hours, about 14 hours, or about 24 hours after the eniluracil is administered. 
     
     
         45 - 46 . (canceled) 
     
     
         47 . The method of  claim 43 , wherein the capecitabine is administered at a dose such that at its time of administration the capecitabine is present in the patient in at least 2-fold excess, in at least 3-fold excess, or in at least five-fold excess of the DPD inhibitor. 
     
     
         48 . (canceled) 
     
     
         49 . The method of  claim 43 , wherein the capecitabine is administered at a dose between about 1.5-4 mg/m 2 . 
     
     
         50 - 57 . (canceled) 
     
     
         58 . The method of  claim 1 , wherein the doses of the DPD inhibitor and the 5-FU or 5-FU prodrug are at a ratio of 1:3 to 1:20, a ratio of 1:5 to 1:15, or a ratio of 1:8 to 1:12. 
     
     
         59 - 60 . (canceled)