Dosing of Cabozantinib Formulations

Abstract

The invention relates to administration of various pharmaceutical formulations of N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, (cabozantinib) a c-Met inhibitor, and its metabolites, to achieve desirable pharmacokinetic and pharmacodynamic effects.

1 . A pharmaceutical formulation comprising a physiologically effective amount of cabozantinib, wherein oral administration of said pharmaceutical formulation to a selected human subject group produces in said selected human subject group:
 an average cabozantinib plasma area under the curve (average AUC) of at least 60,000 ng·h/mL per each 140 mg dosage of cabozantinib delivered;   an average maximum cabozantinib blood plasma concentration (average C max ) of at least 1000 ng/mL per each 140 mg dosage of cabozantinib delivered; and   a ratio of AUC (cabozantinib) to the AUC of the sum of cabozantinib plus measured cabozantinib metabolites:
   AUC (Cabozantinib)/AUC (Cabozantinib+Measured Metabolites) 
   
       of at least 0.25;
 wherein the AUC is measured from time zero to the time of last measurable concentration. 
 
     
     
         2 . A pharmaceutical formulation comprising a physiologically effective amount of cabozantinib, wherein oral administration of said pharmaceutical formulation to a selected human subject group produces in said selected human subject group:
 a steady state area under the curve for cabozantinib (average AUC) of at least 35,000 ng·h/mL for a formulation comprising 100 mg of cabozantinib delivered once daily;   an average maximum cabozantinib blood plasma concentration (average C max ) of at least 2400 ng/mL per each 100 mg dosage of cabozantinib delivered;   an average minimum cabozantinib blood plasma concentration (average C max ) of at least 1100 ng/mL per each 100 mg dosage of cabozantinib delivered; and   a ratio of AUC (cabozantinib) to the AUC of the sum of cabozantinib plus measured cabozantinib metabolites:
   AUC (Cabozantinib)/AUC (Cabozantinib+Measured Metabolites) 
   
       of at least 0.35;
 wherein the AUC is measured on day 22. 
 
     
     
         3 . The pharmaceutical formulation of  claims 1 - 2 , wherein the measured metabolites are selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein GA is a glucuronic acid moiety, 
     
     
         4 . The pharmaceutical formulation of  claims 1 - 2 , wherein the measured metabolites comprise one or more of: 
       
         
           
           
               
               
           
         
       
     
     
         5 . A method of treating cancer in a human patient, comprising orally administering to said patient a pharmaceutical formulation comprising a physiologically effective amount of cabozantinib at such a rate to achieve:
 an average cabozantinib plasma area under the curve (average AUC) of at least 60,000 ng·h/mL per each 140 mg dosage of cabozantinib delivered;   an average maximum cabozantinib blood plasma concentration (average C max ) of at least 1000 ng/mL per each 140 mg dosage of cabozantinib delivered; and   a ratio of AUC (cabozantinib) to the AUC of the sum of cabozantinib plus measured cabozantinib metabolites:
   AUC (Cabozantinib)/AUC (Cabozantinib+Measured Metabolites) 
   
       of at least 0.25;
 wherein the AUC is measured from time zero to the time of last measurable concentration. 
 
     
     
         6 . A method of treating cancer in a human patient, comprising orally administering to said patient a pharmaceutical formulation comprising a physiologically effective amount of cabozantinib at such a rate to achieve:
 a steady state area under the curve for cabozantinib (average AUC) of at least 35,000 ng·h/mL for a formulation comprising 100 mg of cabozantinib delivered once daily;   an average maximum cabozantinib blood plasma concentration (average C max ) of at least 2400 ng/mL per each 100 mg dosage of cabozantinib delivered;   an average minimum cabozantinib blood plasma concentration (average C max ) of at least 1100 ng/mL per each 100 mg dosage of cabozantinib delivered; and   a ratio of AUC (cabozantinib) to the AUC of the sum of cabozantinib plus measured cabozantinib metabolites:
   AUC (Cabozantinib)/AUC (Cabozantinib+Measured Metabolites) 
   
       of at least 0.35;
 wherein the AUC is measured on day 22. 
 
     
     
         7 . The method of  claims 5 - 6 , wherein the measured metabolites are selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein GA is a glucuronic acid moiety, 
     
     
         8 . The method of wherein the measured metabolites comprise one or more of: 
       
         
           
           
               
               
           
         
       
     
     
         9 . The method of  claims 5 - 8 , wherein the cancer is selected from ovarian cancer, lung cancer, medullary thyroid cancer, liver cancer, gastrointestinal cancer, pancreatic cancer, bone cancer, hematologic cancer, skin cancer, kidney cancer, breast cancer, colon cancer, and fallopian tube cancer.