Prevention of hiv-infection

Abstract

This invention relates to the use of a parenteral formulation comprising the NNRTI TMC278 for the long term prevention of HIV infection in a subject at risk of being infected by HIV, which comprises the intermittent administration of the said formulation at long time intervals.

1 . A method for the long term prevention of HIV infection in an individual at risk of being infected by HIV comprising administrating to such an individual, intermittently at a time interval of at least one week, a parenteral formulation containing an effective amount of the HIV inhibitor 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]-amino]benzonitrile, the E isomeric form thereof or the Z-isomeric form thereof; or a pharmaceutically acceptable acid-addition salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         2 . The method according to  claim 1  wherein the formulation is administered once every two weeks. 
     
     
         3 . The method according to  claim 1  wherein the formulation is administered once every month. 
     
     
         4 . The method according to  claim 1  wherein the effective amount of 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]-amino]benzonitrile, the E isomeric form thereof or the Z-isomeric form thereof; or a pharmaceutically acceptable acid-addition salt thereof, in the parenteral formulation is selected such that the blood plasma concentration of 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]-amino]benzonitrile, the E isomeric form thereof or the Z-isomeric form thereof; or a pharmaceutically acceptable acid-addition salt thereof, is kept during a prolonged period of time at a level between a maximum blood plasma level which is the blood plasma level that causes significant side effects and the minimum blood plasma level that is the lowest blood plasma level that causes the HIV inhibitor to provide effective prevention of HIV infection. 
     
     
         5 . The method according to  claim 1  wherein the blood plasma level is kept at a level equal to or above about 15 ng/ml. 
     
     
         6 . The method according to  claim 1  wherein the blood plasma level is kept at a level equal to or above about 20 ng/ml. 
     
     
         7 . The method according to  claim 1  wherein the formulation is administered subcutaneously or intramuscularly. 
     
     
         8 . The method according to  claim 1  wherein the HIV inhibitor 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]-amino]benzonitrile is in base-form. 
     
     
         9 . The method of maintaining a blood plasma level of 4-1000 ng/ml of 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile, the E isomeric form thereof or the Z-isomeric form thereof; or a pharmaceutically acceptable acid-addition salt thereof, in an individual at risk of being infected with HIV, comprising administering to such an individual, intermittently at a time interval of at least one week, a formulation for subcutaneous or intramuscular administration, said formulation comprising a pharmaceutically acceptable carrier and a dose calculated on a basis of 0.2 mg/day to 50 mg/day of 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile, the E isomeric form thereof or the Z-isomeric form thereof; or a pharmaceutically acceptable acid-addition salt thereof. 
     
     
         10 . The method according to  claim 9  wherein the formulation is administered at a time interval of 3, 4, 5 or 6 weeks. 
     
     
         11 . The method according to  claim 9  wherein the formulation is administered at a time interval of 1, 2, or 3 months. 
     
     
         12 . The method according to  claim 9  wherein the formulation is administered once every month. 
     
     
         13 . The method according to  claim 9  wherein the formulation is administered once every three months. 
     
     
         14 . The method according to  claim 9  wherein the blood plasma level of 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile, the E isomeric form thereof or the Z-isomeric form thereof; or a pharmaceutically acceptable acid-addition salt thereof is maintained at a level equal to or above 15 ng/ml. 
     
     
         15 . The method according to  claim 9  wherein the blood plasma level of 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile, the E isomeric form thereof or the Z-isomeric form thereof; or a pharmaceutically acceptable acid-addition salt thereof is maintained at a level equal to or above 20 ng/ml. 
     
     
         16 . The method according to  claim 9  wherein the blood plasma level of 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile, the E isomeric form thereof or the Z-isomeric form thereof; or a pharmaceutically acceptable acid-addition salt thereof is maintained at a level equal to or above 40 ng/ml. 
     
     
         17 . The method according to  claim 9  wherein the blood plasma level of 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile, the E isomeric form thereof or the Z-isomeric form thereof; or a pharmaceutically acceptable acid-addition salt thereof is maintained at a level below 40 ng/ml and above 4 ng/ml. 
     
     
         18 . The method according to  claim 9  wherein the formulation is an injectable solution and the carrier comprises sterile water and a solubilizer or a surfactant. 
     
     
         19 . The method according to  claim 18  wherein the solubilizer is a cyclodextrin or cyclodextrin derivative or a polyethylene glycol. 
     
     
         20 . The method according to  claim 9 , wherein 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethyl-phenyl]amino]-2-pyrimidinyl]amino]benzonitrile, the E isomeric form thereof or the Z-isomeric form thereof; or a pharmaceutically acceptable acid-addition salt thereof is in base-form. 
     
     
         21 . The method according to  claim 9  wherein 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethyl-phenyl]amino]-2-pyrimidinyl]amino]benzonitrile, the E isomeric form thereof or the Z-isomeric form thereof; or a pharmaceutically acceptable acid-addition salt thereof occurs in its E-isomeric form. 
     
     
         22 . The method according to  claim 20  wherein the base form of 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile, the E isomeric form thereof or the Z-isomeric form thereof, occurs in its E-isomeric form.