Methods and compositions for the assessment of drug response

Abstract

The present invention provides methods for predicting or determining a subject's response to an antiplatelet agent, and methods for determining a subject's suitability to a treatment regime or intervention for a disease associated with platelet aggregation, using analysis of genetic polymorphisms. The present invention also relates to the use of genetic polymorphisms in assessing a subject's response to an antiplatelet agent. Nucleotide probes and primers, kits, and microarrays suitable for such assessment are also provided

We claim: 
     
         1 . A method comprising:
 a) analyzing a sample from a subject with a SNP detection assay to determine that said subject has a 636G>A (CYP2C19*3) polymorphism and/or a 19154G>A (CYP2C19*2) polymorphism, thereby generating a CYP2C19 genetic analysis result; and   b) processing said CYP2C19 genetic analysis result with a computer system to generate an outcome that indicates that said subject should receive:
 i) a loading dose of clopidogrel on the first day of treatment being in a range of from above 600 mg to about 1800 mg, and 
 ii) a maintenance dosage of said clopidogrel on subsequent days of treatment, said maintenance dosage being in the range of from above 50 mg to about 200 mg. 
   
     
     
         2 . The method of  claim 1 , wherein it is determined that said subject has said CYP2C19*3 polymorphism. 
     
     
         3 . The method of  claim 1 , wherein it is determined that said subject has said CYP2C19*2 polymorphism. 
     
     
         4 . The method of  claim 1 , wherein said loading dose is in a range from above 900 mg to about 1500 mg. 
     
     
         5 . The method of  claim 1 , wherein said loading dose is about 1200 mg. 
     
     
         6 . The method of  claim 1 , wherein said maintenance dose is between about 75 mg and about 150 mg. 
     
     
         7 . The method of  claim 1 , wherein said maintenance dose is about 150 mg. 
     
     
         8 . A method comprising:
 a) analyzing a sample from a subject with a SNP detection assay to determine that said subject has a 636G>A (CYP2C19*3) polymorphism and/or a 19154G>A (CYP2C19*2) polymorphism, thereby generating a CYP2C19 genetic analysis result; and   b) processing said CYP2C19 genetic analysis result with a computer system to generate an outcome that indicates that said subject should receive:
 i) a first loading dosage of clopidogrel on the first day of treatment, said first loading dose being in a range of from above 300 mg to about 900 mg, 
 ii) a second loading dosage of clopidogrel on said first day of treatment, said second loading dose being in a range of from above 300 mg to about 900 mg, and 
 iii) a maintenance dosage of clopidogrel on subsequent days of treatment, said maintenance dosage being in the range of from above 50 mg to about 200 mg. 
   
     
     
         9 . The method of  claim 8 , wherein it is determined that said subject has said CYP2C19*3 polymorphism. 
     
     
         10 . The method of  claim 8 , wherein it is determined that said subject has said CYP2C19*2 polymorphism. 
     
     
         11 . A method of treating a subject identified as a clopidogrel poor or non-responder, comprising:
 a) administering to the subject a loading dosage of clopidogrel on the first day of treatment, said loading dose being in a range of from above 600 mg to about 1800 mg; and   b) administering to said subject a maintenance dosage of clopidogrel on subsequent days of treatment, said maintenance dosage being in the range of from above 50 mg to about 200 mg.   
     
     
         12 . The method of  claim 11 , wherein said subject is identified as possessing the CYP2C19*2 polymorphism. 
     
     
         13 . The method of  claim 11 , wherein said subject is identified as possessing the CYP2C19*3 polymorphism. 
     
     
         14 . The method of  claim 11 , wherein said loading dose is in a range from above 900 mg to about 1500 mg. 
     
     
         15 . The method of  claim 11 , wherein said loading dose is about 1200 mg. 
     
     
         16 . The method of  claim 11 , wherein said maintenance dose is between about 75 mg and about 150 mg. 
     
     
         17 . A method of treating a subject identified as a clopidogrel poor or non-responder, comprising:
 a) administering to the subject a first loading dosage of clopidogrel on the first day of treatment, said first loading dose being in a range of from above 300 mg to about 900 mg;   b) administering to the subject a second loading dosage of clopidogrel on said first day of treatment, said second loading dose being in a range of from above 300 mg to about 900 mg; and   c) administering to said subject a maintenance dosage of clopidogrel on subsequent days of treatment, said maintenance dosage being in the range of from above 50 mg to about 200 mg.   
     
     
         18 . The method of  claim 17 , wherein said second loading dose is administered at least about 30 minutes after said first loading dose. 
     
     
         19 . The method of  claim 17 , wherein said second loading dose is administered at between about 30 minutes and 4 hours after said first loading dose. 
     
     
         20 . The method of  claim 17 , wherein said first and second loading doses are each about 600 mg. 
     
     
         21 . The method of  claim 17 , wherein said subject is identified as possessing the CYP2C19*2 polymorphism. 
     
     
         22 . The method of  claim 17 , wherein said subject is identified as possessing the CYP2C19*3 polymorphism. 
     
     
         23 . The method of  claim 17 , wherein said maintenance dose is between about 75 mg and about 150 mg. 
     
     
         24 . A kit for providing a plurality of dosage forms of clopidogrel comprising:
 a) a loading dose of said clopidogrel in a range of from above 600 mg to about 1800 mg, and   b) a maintenance dose of said clopidogrel in a range of from above 50 mg to about 200 mg.   
     
     
         25 . The kit of  claim 24 , further comprising:
 c) instructions for administering said clopidogrel to a patient, wherein said instructions indicate that a patient that possess the CYP2C19*2 and/or *3 polymorphisms should receive:
 i) said loading dose of said clopidogrel on the first day of treatment, and 
 ii) said maintenance dosage of said clopidogrel on subsequent days of treatment.