Oral octreotide administered in combination with other therapeutic agents

Abstract

This invention relates to combination therapy of a subject suffering from acromegaly. The method of treatment comprises administration to the subject of a therapeutically effective amount of oral somatostatin receptor ligand (SRL) e.g. octreotide in combination with a therapeutically effective amount of a dopamine agonist and/or a growth hormone receptor antagonist and/or a selective estrogen receptor modulator (SERM) and/or a 2nd somatostatin receptor ligand (SRL).

1 . A method of treatment of a subject suffering from acromegaly which comprises administration to the subject of a therapeutically effective amount of an oral somatostatin receptor ligand (SRL) in combination with a therapeutically effective amount of a dopamine agonist and/or a growth hormone receptor antagonist and/or a 2 nd  somatostatin receptor ligand (SRL) and/or a selective estrogen receptor modulator (SERM). 
     
     
         2 . The method of treatment of  claim 1  wherein the oral somatostatin receptor ligand (SRL) is octreotide or lanreotide or pasireotide. 
     
     
         3 . The method of treatment of  claim 2  wherein the oral somatostatin receptor ligand (SRL) is octreotide. 
     
     
         4 . The method of treatment of  claims 1 - 3  where the level of IGF-1 in the subject is only partially controlled on SRL alone. 
     
     
         5 . The method of treatment of  claims 1 - 4  where the level of IGF-1 in the subject is only partially controlled on dopamine agonist alone. 
     
     
         6 . The method of  claims 1 - 5  wherein the dopamine agonist is cabergoline. 
     
     
         7 . The method of  claims 1 - 6  wherein the dopamine agonist is bromocriptine. 
     
     
         8 . The method of  claims 1 - 3  wherein the growth hormone receptor antagonist is pegvisomant or ATL1103. 
     
     
         9 . The method of  claims 1 - 8  wherein the administration of octreotide comprises about 5 mg to about 120 mg of octreotide daily. 
     
     
         10 . The method of  claim 9  wherein the administration of octreotide comprises about 40 to about 80 mg of octreotide daily. 
     
     
         11 . The method of  claim 9  wherein the administration of octreotide comprises about 10 to about 80 mg of octreotide daily, such as 10, 20, 30, 40, 50, 60, 70 or 80 mg daily. 
     
     
         12 . The method of  claim 9  wherein the administration of octreotide comprises 80 mg of octreotide daily. 
     
     
         13 . The method of  claim 6  wherein the administration of cabergoline comprises about 0.2 to about 5 mg of cabergoline weekly. 
     
     
         14 . The method of  claim 6  wherein the administration of cabergoline comprises about 0.4 to about 4 mg of cabergoline weekly, such as 1, 2, 3, 3.5 or 4 mg of cabergoline weekly. 
     
     
         15 . The method of  claim 6  wherein the administration of cabergoline comprises about 0.2 to about 1 mg of cabergoline weekly, such as 0.2, 0.40, 0.6 0.8 or 1.0 mg of cabergoline weekly. 
     
     
         16 . The method of  claim 6  wherein the administration of cabergoline is bi-weekly. 
     
     
         17 . The method of  claim 13  wherein the administration of cabergoline is gradually increased from 0.5 mg×2 per week for first two weeks, 1 mg×2 per week for additional two weeks, followed by 1.5 mg×2 per week for additional two weeks reaching a maintenance dose of 1.75 mg×2 per week. 
     
     
         18 . The method of  claim 14  wherein the administration of cabergoline is a maintenance dose of 3.0 mg to 3.5 mg weekly. 
     
     
         19 . The method of  claim 8  wherein the administration of pegvisomant comprises about 2 mg to about 60 mg of pegvisomant daily or once, twice, three, four, five or six times per week. 
     
     
         20 . The method of  claim 8  wherein the administration of pegvisomant comprises about 10 to about 20 mg of pegvisomant daily or once, twice, three, four, five or six times per week. 
     
     
         21 . The method of  claim 8  wherein the administration of pegvisomant comprises about 2 to about 10 mg of pegvisomant daily or once, twice, three, four, five or six times per week, such as 2, 4, 6, 8 or 10 mg of pegvisomant daily or once, twice, three, four, five or six times per week. 
     
     
         22 . The method of  claims 1 ,  4  and  5  wherein the SERM is clomiphene. 
     
     
         23 . The method of  claim 22  wherein the administration of octreotide comprises about 5 mg to about 120 mg of octreotide daily. 
     
     
         24 . The method of  claim 23  wherein the administration of octreotide comprises about 40 to about 100 mg of octreotide daily. 
     
     
         25 . The method of  claim 24  wherein the administration of octreotide comprises 80 mg of octreotide daily. 
     
     
         26 . The method of  claims 22 - 25  wherein the administration of clomiphene comprises 10-200 mg per day. 
     
     
         27 . The method of  claim 26  wherein the administration of clomiphene comprises 50 mg per day. 
     
     
         28 . The method of  claims 1 - 3  wherein the 2 nd  somatostatin receptor ligand is a long-acting injectable formulation. 
     
     
         29 . The method of treatment of  claim 28  wherein the oral somatostatin receptor ligand (SRL) is octreotide or lanreotide or pasireotide. 
     
     
         30 . The method of treatment of  claim 29  wherein the oral somatostatin receptor ligand (SRL) is octreotide. 
     
     
         31 . The method of  claim 30  wherein the 2 nd  somatostatin receptor ligand is a long-acting injectable formulation which is administered every four weeks. 
     
     
         32 . The method of  claims 30 - 31  wherein the administration of oral octreotide is in order to treat breakthrough acromegaly symptoms. 
     
     
         33 . The method of  claims 30 - 32  wherein the administration of oral octreotide comprises about 10 to about 80 mg of octreotide daily, such as 10, 20, 30, 40, 50, 60, 70 or 80 mg daily. 
     
     
         34 . The method of  claims 30 - 33  wherein the octreotide is administered on an “as needed” basis. 
     
     
         35 . The method of  claims 30 - 33  wherein the octreotide is administered on a regular basis. 
     
     
         36 . The method of  claim 30 - 33  wherein the octreotide is administered on a daily basis. 
     
     
         37 . The method of  claim 36  wherein the octreotide is administered on a daily basis toward the end of the dosing interval wherein the long-acting somatostatin receptor ligand was administered. 
     
     
         38 . The method of  claim 36  wherein the octreotide is administered on a daily basis during the fourth week after the long-acting somatostatin receptor ligand was administered. 
     
     
         39 . A unit dosage formulation for oral administration comprising an oral SRL and a dopamine agonist. 
     
     
         40 . The unit dosage formulation of  claim 39  wherein the dopamine agonist is cabergoline. 
     
     
         41 . The unit dosage formulation of  claim 39  wherein the oral SRL is octreotide. 
     
     
         42 . The unit dosage formulation of  claim 40  which comprises 5-120 mg octreotide and 0.01-1.0 mg cabergoline. 
     
     
         43 . A unit dosage formulation for oral administration comprising an oral SRL and SERM. 
     
     
         44 . The unit dosage formulation of  claim 43  wherein the SERM is clomiphene. 
     
     
         45 . The unit dosage formulation of  claim 43  wherein the oral SRL is octreotide. 
     
     
         46 . The unit dosage formulation of  claim 45  which comprises 5-120 mg octreotide and clomiphene. 
     
     
         47 . The unit dosage formulation of  claim 45  which comprises 5-120 mg octreotide and 5-200 mg clomiphene. 
     
     
         48 . A unit dosage formulation for oral administration comprising an SRL and a dopamine agonist and a SERM. 
     
     
         49 . The unit dosage formulation of  claim 48  wherein the dopamine agonist is cabergoline. 
     
     
         50 . The unit dosage formulation of  claim 48  wherein the SERM is clomiphene. 
     
     
         51 . The unit dosage formulation of  claim 48  wherein the oral SRL is octreotide 
     
     
         52 . The unit dosage formulation of  claim 48  wherein the oral SRL is octreotide and the dopamine agonist is cabergoline and the SERM is clomiphene. 
     
     
         53 . The unit dosage formulation of  claims 47 - 52  which comprises 5-120 mg octreotide. 
     
     
         54 . The unit dosage formulation of  claims 47 - 52  which comprises 0.01-1.0 mg cabergoline. 
     
     
         55 . The unit dosage formulation of  claims 47 - 52  which comprises 5-200 mg clomiphene. 
     
     
         56 . The unit dosage formulation of  claims 47 - 52  which comprises 5-120 mg octreotide, 0.01-1.0 mg cabergoline and 5-200 mg clomiphene. 
     
     
         57 . A method of treatment of a subject suffering from acromegaly which comprises administration to the subject of a therapeutically effective amount of an oral SRL in combination with a therapeutically effective amount of a dopamine agonist and/or a growth hormone receptor antagonist and/or a SERM. 
     
     
         58 . The method of  claim 57  wherein the oral SRL is selected from octreotide, lanreotide and pasireotide. 
     
     
         59 . The method of  claims 57 - 58  wherein the dopamine agonist is cabergoline. 
     
     
         60 . The method of  claims 57 - 58  wherein the dopamine agonist is bromocriptine. 
     
     
         61 . The method of  claims 57 - 58  wherein the growth hormone receptor antagonist is pegvisomant. 
     
     
         62 . The method of  claims 57 - 58  wherein the SERM is clomiphene. 
     
     
         63 . A method of treating acromegaly in a subject comprising the following steps: administration of oral octreotide with an initial dose of 20 mg BID;
 receiving information regarding blood levels of IGF-1 and/or clinical symptoms and in response to blood levels of IGF-1 and/or clinical symptoms, evaluating the course of treatment,
 wherein if blood levels of IGF-1 are normal and/or clinical symptoms are controlled and/or response level (biochemical and symptomatic response) is maintained, maintain oral octreotide dosage at 20 mg BID; and 
 wherein if IGF-1 levels are increased, or in case of symptomatic exacerbation, dosage of oral octreotide may be adjusted to 60 mg daily (40 mg morning+20 mg evening); continuing to receive information regarding blood levels of IGF-1 and/or clinical symptoms, and evaluating the course of treatment (e.g., applying the above algorithm for maintaining or increasing the dose up to 40 mg BID); 
 wherein if the blood levels of IGF-1 and/or clinical symptoms indicate the subject has failed to respond to octreotide capsules 80 mg for at least two weeks treatment, or subjects having inadequate biochemical control on octreotide capsules 80 mg for at least two weeks treatment, co-administering of octreotide capsules 80 mg with a second therapeutic agent (e.g., a dopamine agonist such as cabergoline or a SERM such as clomiphene). 
   
     
     
         64 . The method of  claim 63  wherein the second therapeutic agent is cabergoline, preferably administered up to 3.5 mg/week. 
     
     
         65 . The method of  claim 64  wherein the cabergoline may be administered twice weekly, preferably with dinner, with a fixed titration algorithm every two weeks, starting with 0.5 mg×2/week at the first two weeks, 1 mg×2/week for additional two weeks, followed by 1.5 mg×2/week, and increase to a maximum of 1.75 mg×2/week. 
     
     
         66 . The method of  claim 64  wherein the daily dose of cabergoline can be up to 0.5 mg/day (3.5 mg/week), or up to 1 mg×3/week (3.0 mg/week). 
     
     
         67 . The method of  claims 63 - 66  wherein the combination therapy of oral octreotide and second therapeutic agent (e.g. cabergoline) is maintained.