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.

1 - 20 . (canceled) 
     
     
         21 - 33 . (canceled) 
     
     
         34 . A method of treating a disease associated with platelet aggregation in 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.   
     
     
         35 . The method of  claim 34 , wherein said subject is identified as possessing the CYP2C19*2 polymorphism. 
     
     
         36 . The method of  claim 34 , further comprising, prior to step a), testing a sample from said subject and determining that said subject possesses the CYP2C19*2 polymorphism. 
     
     
         37 . The method of  claim 34 , wherein said subject is identified as possessing the CYP2C19*3 polymorphism. 
     
     
         38 . The method of  claim 34 , further comprising, prior to step a), testing a sample from said subject and determining that said subject possesses the CYP2C19*3 polymorphism. 
     
     
         39 . The method of  claim 34 , wherein said loading dose is in a range from above 900 mg to about 1500 mg. 
     
     
         40 . The method of  claim 34 , wherein said loading dose is about 1200 mg. 
     
     
         41 . The method of  claim 34 , wherein said maintenance dose is between about 75 mg and about 150 mg. 
     
     
         42 . The method of  claim 34 , wherein said maintenance dose is about 150 mg. 
     
     
         43 . A method of treating a disease associated with platelet aggregation in 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.   
     
     
         44 . The method of  claim 43 , wherein said second loading dose is administered at least about 30 minutes after said first loading dose. 
     
     
         45 . The method of  claim 43 , wherein said second loading dose is administered at between about 30 minutes and 4 hours after said first loading dose. 
     
     
         46 . The method of  claim 43 , wherein said second loading dose is administered at between about 1 hour and 2.5 hours after said first loading dose. 
     
     
         47 . The method of  claim 43 , wherein said first loading dose is about 600 mg. 
     
     
         48 . The method of  claim 43 , wherein said second loading dose is about 600 mg. 
     
     
         49 . The method of  claim 43 , wherein said first and second loading doses are each about 600 mg. 
     
     
         50 . The method of  claim 43 , wherein said subject is identified as possessing the CYP2C19*2 polymorphism. 
     
     
         51 . The method of  claim 43 , further comprising, prior to step a), testing a sample from said subject and determining that said subject possesses the CYP2C19*2 polymorphism. 
     
     
         52 . The method of  claim 43 , wherein said subject is identified as possessing the CYP2C19*3 polymorphism. 
     
     
         53 . The method of  claim 43 , further comprising, prior to step a), testing a sample from said subject and determining that said subject possesses the CYP2C19*3 polymorphism. 
     
     
         54 . The method of  claim 43 , wherein said maintenance dose is between about 75 mg and about 150 mg. 
     
     
         55 . The method of  claim 43 , wherein said maintenance dose is about 150 mg. 
     
     
         56 . A method of predicting or determining a subject's level of metabolism for clopidogrel, comprising: analyzing a sample from said subject for:
 i) the presence or absence of the −806C/T polymorphism in the CYP2C19 gene (CYP2C19*17 polymorphism),   ii) the presence or absence of the 636 G>A polymorphism in said CYP2C19 gene (CYP2C19*3 polymorphism), and   iii) the presence or absence of the 19154G/A polymorphism in said CYP2C19 gene (CYP2C19*2 polymorphism).   
     
     
         57 . A method of predicting or determining a subject's level of metabolism for clopidogrel, comprising: correlating the presence or absence of the 636 G>A polymorphism in the CYP2C19 gene (CYP2C19*3 polymorphism), as determined from a sample from said subject, with said subject's level of metabolism for said clopidogrel, wherein the presence of said CYP2C19*3 polymorphism indicates that said subject has an decreased level of metabolism for said clopidogrel. 
     
     
         58 . The method of  claim 57 , further comprising, prior to said correlating, analyzing said sample from said subject for the presence or absence of said 636 G>A polymorphism in said CYP2C19 gene.