Dosing regimen for a selective s1p1 receptor agonist

Abstract

The present invention relates to a dosing regimen for a selective S1P 1 receptor agonist, whereby the selective S1P 1 receptor agonist is administered to a subject in such a way that during the initial treatment phase the selective S1P 1 receptor agonist is administered at a dose which induces desensitization of the heart wherein said dose is below the target dose, and at a dosing frequency that sustains desensitization of the heart, until no further acute heart rate reduction occurs, followed by dose up-titration to the target dose of the selective S1P 1 receptor agonist.

1 . A method for administering a selective S1P 1  receptor agonist or a pharmaceutically acceptable salt thereof to a subject in need thereof wherein during an initial treatment phase the selective S1P 1  receptor agonist or pharmaceutically acceptable salt thereof is administered at a dose which induces desensitization of the heart to acute heart rate reduction said dose being below the target dose, and at a dosing frequency that sustains desensitization of the heart, until no further acute heart rate reduction occurs, followed by dose up-titration to the target dose of the selective S1P 1  receptor agonist or pharmaceutically acceptable salt thereof. 
     
     
         2 . The method for administering a selective S1P 1  receptor agonist or pharmaceutically acceptable salt thereof according to  claim 1 , wherein the initial dose below the target dose is between 2- to 5-fold lower than the target dose. 
     
     
         3 . The method for administering a selective S1P 1  receptor agonist or pharmaceutically acceptable salt thereof according to  claim 1 , wherein the initial dose below the target dose is between 5- to 16-fold lower than the target dose. 
     
     
         4 . The method for administering a selective S1P 1  receptor agonist or pharmaceutically acceptable salt thereof to  claim 1 , wherein the dose below the target dose is administered to the subject during the initial 2 to 4 days of the treatment. 
     
     
         5 . The method for administering a selective S1P 1  receptor agonist or pharmaceutically acceptable salt thereof according to  claim 1  whereby wherein the dose below the target dose is administered at a dosing frequency of once or twice daily. 
     
     
         6 - 14 . (canceled) 
     
     
         15 . A method of administering to a subject in need thereof a medication comprising a S1P receptor agonist, whereby said S1P receptor modulator or agonist is given at a dosage lower than the standard daily dosage of said S1P receptor modulator or agonist during the initial period of treatment and then the dosage is increased, up to the standard daily dosage of said S1P receptor agonist. 
     
     
         16 . The method according to  claim 15 , wherein the medication is for the treatment of an autoimmune condition. 
     
     
         17 . The method according to  claim 16 , wherein the autoimmune condition is multiple sclerosis. 
     
     
         18 . The method according to  claim 15 , wherein a sub-therapeutic dose of the S1P receptor agonist that is 80 fold less, 40 fold less, 10-fold less or 4-fold less than the standard daily dosage is administered during the initial period of treatment. 
     
     
         19 . The method according to  claim 15  wherein, during the initial period of treatment, the administered dosage is increased stepwise. 
     
     
         20 . The method according to  claim 19 , wherein the administered dosage is increased stepwise such that the dosage administered on a specific day during the initial period of treatment is the sum of the dosages administered on the previous two days within a range ±40%. 
     
     
         21 . A method for treating a subject in need thereof comprising administering a S1P receptor agonist which induces a negative chronotropic effect in heart rate, to the subject at a daily dosage which is lower than the standard daily therapeutic dosage during an initial period of treatment and thereafter commencing the administration of said S1P receptor modulator or agonist at the required standard daily therapeutic dosage. 
     
     
         22 . The method of  claim 21 , wherein the patient is suffering from an autoimmune condition. 
     
     
         23 . The method of  claim 22  wherein the autoimmune condition is multiple sclerosis. 
     
     
         24 . A method of ameliorating or preventing a negative chronotropic side effect associated with a treatment using an S1P agonist of a subject suffering from an autoimmune disease, comprising administering to the subject in need thereof, said S1P receptor agonist at a daily dosage which is lower than the standard daily dosage during an initial treatment period and raising the daily dosage stepwise up to the standard daily dosage. 
     
     
         25 . The method according to  claim 21 , comprising administering to the subject, a S1P receptor agonist at a daily dosage which is lower than the standard daily dosage during the first 10 days and raising the daily dosage stepwise up to the standard daily dosage. 
     
     
         26 . The method according to  claim 24 , comprising administering to the subject, a S1P receptor agonist at a daily dosage which is lower than the standard daily dosage during the first 10 days and raising the daily dosage stepwise up to the standard daily dosage. 
     
     
         27 . A method of administering to a subject in need thereof a medication comprising a S1P 1  receptor agonist, whereby said S1P 1  receptor modulator or agonist is given at a dosage lower than the standard daily dosage of said S1P 1  receptor modulator or agonist during the initial period of treatment and then the dosage is increased, up to the standard daily dosage of said S1P 1  receptor agonist. 
     
     
         28 . The method according to  claim 27 , wherein the medication is for the treatment of an autoimmune condition. 
     
     
         29 . The method according to  claim 28 , wherein the autoimmune condition is multiple sclerosis. 
     
     
         30 . The method according to  claim 27 , wherein a sub-therapeutic dose of the S1P 1  receptor agonist that is 80 fold less, 40 fold less, 10-fold less or 4-fold less than the standard daily dosage is administered during the initial period of treatment. 
     
     
         31 . The method according to  claim 27 , wherein, during the initial period of treatment, the administered dosage is increased stepwise. 
     
     
         32 . The method according to  claim 31 , wherein the administered dosage is increased stepwise such that the dosage administered on a specific day during the initial period of treatment is the sum of the dosages administered on the previous two days within a range ±40%. 
     
     
         33 . A method for treating a subject in need thereof comprising administering a S1P 1  receptor agonist which induces a negative chronotropic effect in heart rate, to the subject at a daily dosage which is lower than the standard daily therapeutic dosage during an initial period of treatment and thereafter commencing the administration of said S1P 1  receptor modulator or agonist at the required standard daily therapeutic dosage. 
     
     
         34 . The method of  claim 33 , wherein the patient is suffering from an autoimmune condition. 
     
     
         35 . The method of  claim 34  wherein the autoimmune condition is multiple sclerosis. 
     
     
         36 . A method of ameliorating or preventing a negative chronotropic side effect associated with a treatment using an S1P 1  agonist of a subject suffering from an autoimmune disease, comprising administering to the subject in need thereof, said S1P 1  receptor agonist at a daily dosage which is lower than the standard daily dosage during an initial treatment period and raising the daily dosage stepwise up to the standard daily dosage. 
     
     
         37 . The method according to  claim 33 , comprising administering to the subject, a S1P 1  receptor agonist at a daily dosage which is lower than the standard daily dosage during the first 10 days and raising the daily dosage stepwise up to the standard daily dosage. 
     
     
         38 . The method according to  claim 36 , comprising administering to the subject, a S1P 1  receptor agonist at a daily dosage which is lower than the standard daily dosage during the first 10 days and raising the daily dosage stepwise up to the standard daily dosage.