Dosage regimes for the administration of glucagon-like-peptide-2 (glp-2) analogues

Abstract

Dosage regimes for the administration of glucagon-like-peptide-2 (GLP-2) analogues and their medical use are disclosed, for example in the treatment and/or prevention of stomach and bowel-related disorders and for ameliorating side effects of chemotherapy and radiation therapy. Dosage regimes for the administration of glucagon-like-peptide-2 (GLP-2) analogues for inducing longitudinal growth of the intestines are described, for example for the treatment of patients with short bowel syndrome (SBS). Medical uses for adjusting the volume of parenteral support (PS) provided to subjects receiving treatment with GLP-2 analogues in response to the treatment and to algorithms for determining PS volume changes are also described.

1 . A method for adjusting a parenteral support (PS) volume in a human subject receiving GLP-2 therapy and an amount or volume of parenteral support each week, the method comprising
 (a) calculating a New PS volume according to the formula:
   new PS volume=(current PS volume)−7×(absolute increase in daily urine volume),
 
   wherein
 (i) new PS volume is the calculated weekly volume of parenteral support; 
 (ii) current PS volume is the weekly volume of parenteral support given to the subject at the initiation of GLP-2 therapy; and 
 (iii) absolute increase in daily urine volume is the absolute increase in daily urine volume from a baseline volume measured at the initiation of GLP-2 therapy, and 
   (b) following step (a), administering weekly to the subject the new PS volume of parenteral support.   
     
     
         2 . The method of  claim 1 , wherein the GLP-2 therapy comprises administering to the subject a GLP-2 analogue represented by the formula: 
       
         
           
                 
               
                   R 1 -Z 1 -His-Gly-Glu-Gly-X5-Phe-Ser-Ser-Glu-Leu- 
                 
                     
                 
                   X11-Thr-Ile-Leu-Asp-Ala-Leu-Ala-Ala-Arg-Asp-Phe- 
                 
                     
                 
                   Ile-Ala-Trp-Leu-Ile-Ala-Thr-Lys-Ile-Thr-Asp-Z 2 -R 2   
                 
             
                
                
                
                
                
               
            
           
         
         wherein: 
         R 1  is hydrogen, C 1-4  alkyl, acetyl, formyl, benzoyl or trifluoroacetyl; 
         X5 is Ser or Thr; 
         X11 is Ala or Ser; 
         R 2  is NH 2  or OH; and 
         Z 1  and Z 2  are independently absent or a peptide sequence of 1-6 amino acid units of Lys; 
         or a pharmaceutically acceptable salt or derivative thereof. 
       
     
     
         3 . A method of treating short bowel syndrome in a human patient, said method comprising administering by subcutaneous injection once or twice weekly 10 mg of a GLP-2 analogue into the patient, wherein the GLP-2 analogue is represented by the formula: 
       
         
           
                 
               
                   (SEQ ID NO: 2) 
                 
                 
               
                   H-HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH 2 , 
                 
                     
                 
                   (1848) 
                 
             
                
               
            
             
                
                
                
               
            
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         4 . The method of  claim 3 , wherein the GLP-2 analogue is administered by subcutaneous injection in a fixed dose of 10 mg once weekly. 
     
     
         5 . The method of  claim 3 , wherein the GLP-2 analogue is administered by subcutaneous injection in a fixed dose of 10 mg twice weekly. 
     
     
         6 . The method of  claim 3 , wherein the human patient suffers from SBS-intestinal failure. 
     
     
         7 . The method of  claim 3 , wherein the human patient is a patient being on the border between being having SBS-intestinal insufficiency and SBS-intestinal failure. 
     
     
         8 . The method of  claim 3 , wherein the method delays the development of SBS-intestinal failure in the human patient. 
     
     
         9 . The method of  claim 3 , wherein the method increases the longitudinal growth of the intestines in the human patient. 
     
     
         10 . A method of treating or ameliorating a side effect of chemotherapy or radiation treatment in a human patient, said method comprising administering by subcutaneous injection once or twice weekly 10 mg of a GLP-2 analogue into the patient, wherein the GLP-2 analogue is represented by the formula: 
       
         
           
                 
               
                   (SEQ ID NO: 2) 
                 
                 
               
                   H-HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH 2 , 
                 
                     
                 
                   (1848) 
                 
             
                
               
            
             
                
                
                
               
            
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         11 . The method of  claim 10 , wherein the GLP-2 analogue is administered by subcutaneous injection in a fixed dose of 10 mg once weekly. 
     
     
         12 . The method of  claim 10 , wherein the GLP-2 analogue is administered by subcutaneous injection in a fixed dose of 10 mg twice weekly. 
     
     
         13 . The method of  claim 10 , wherein the patient has a side effect of chemotherapy selected from diarrhoea, abdominal cramping, vomiting, and structural and functional damage of the intestinal epithelium resulting from chemotherapy treatment. 
     
     
         14 . The method of  claim 10 , wherein the administration of the GLP-2 analogue is initiated from 1 to 7 days prior to the initiation of the chemotherapy or radiation treatment. 
     
     
         15 . The method of  claim 10 , wherein the administration of the GLP-2 analogue is initiated the day before or same day as start of chemotherapy or radiation treatment and once or twice weekly thereafter for a period of time. 
     
     
         16 . A method of increasing the longitudinal growth of the intestines in a human patient, said method comprising administering once or twice weekly 10 mg of a GLP-2 analogue to the patient, wherein the GLP-2 analogue is represented by the formula: 
       
         
           
                 
               
                   (SEQ ID NO: 2) 
                 
                 
               
                   H-HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH 2 , 
                 
                     
                 
                   (1848) 
                 
             
                
               
            
             
                
                
                
               
            
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         17 . The method of  claim 16 , wherein the patient suffers from a condition selected from ulcers, digestion disorders, malabsorption syndromes, short-gut syndrome, cul-de-sac syndrome, inflammatory bowel disease, celiac sprue, tropical sprue, hypogammaglobulinemic sprue, enteritis, regional enteritis, ulcerative colitis, small intestine damage, or short bowel syndrome. 
     
     
         18 . The method of  claim 16 , wherein the patient suffers from short bowel syndrome. 
     
     
         19 . The method of  claim 16 , wherein the patient suffers from radiation enteritis, infectious or post-infectious enteritis, or small intestinal damage due to toxic or other chemotherapeutic agents. 
     
     
         20 . The method of  claim 16 , wherein the intestines are increased by at least 30% compared to the control. 
     
     
         21 . The method of  claim 16 , wherein the absorptive capacity of the patient is increased after the administration of the GLP-2 analogue has stopped. 
     
     
         22 . The method of  claim 16 , wherein the patient is treated once or twice weekly for at least 1 to 3 years. 
     
     
         23 . The method of  claim 16 , wherein the patient has SBS-intestinal failure. 
     
     
         24 . The method of  claim 16 , wherein the patient is on the border between being a patient having SBS-intestinal insufficiency and SBS-intestinal failure. 
     
     
         25 . The method of  claim 16 , wherein the method comprises administering the GLP-2 analogue to the patient once weekly. 
     
     
         26 . The method of  claim 16 , wherein the method comprises administering the GLP-2 analogue to the patient twice weekly. 
     
     
         27 . The method of  claim 16 , wherein the method comprises administering a plurality of doses of the GLP-2 analogue to the patient, wherein the doses are separated in time by one week, optionally wherein the doses are administered to the patient for 1 to 3 years. 
     
     
         28 . The method of  claim 16 , wherein the method comprises administering the GLP-2 analogue by injection. 
     
     
         29 . The method of  claim 16 , wherein the 10 mg dose of the GLP-2 analogue is divided into two or three doses that are administered at spatially separated injection sites. 
     
     
         30 . The method of  claim 16 , wherein the method comprises administering the GLP-2 analogue by intravenous injection, subcutaneous injection or intramuscular injection.