PREDICTION OF QT PROLONGATION BASED ON SNP GENOTYPE

• US 20100249188A1
• Filed: 09/10/2008
• Published: 09/30/2010
• Est. Priority Date: 09/10/2007
• Status: Active Grant

• Current Assignee: Vanda Pharmaceuticals Incorporated
• Original Assignee: Vanda Pharmaceuticals Incorporated
• Inventors: Volpi, Simona, Licamele, Louis, Lavedan, Christian, Heaton, Callie Michelle, Mack, Kendra Tomino
• Granted Patent: US 8,652,776 B2
• Time in Patent Office: Days
• US Class Current: 514/321
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 9/06 Antiarrhythmics
• CPC Class Codes: C12Q 1/6883 for diseases caused by alterations of genetic material
• CPC Class Codes: C12Q 2600/106 Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
• CPC Class Codes: C12Q 2600/156 Polymorphic or mutational markers

Abstract

The present invention relates to the prediction of QT prolongation following administration of a compound capable of increasing an individual'"'"'s QT interval based on the individual'"'"'s genotype at one or more single nucleotide polymorphism (SNP) loci and to the treatment of a patient based on such prediction.

Claims

1. A method of predicting an individual'"'"'s QT prolongation following administration of a compound capable of prolonging the individual'"'"'s QT interval, the method comprising:

determining the individual'"'"'s genotype at least one single nucleotide polymorphism (SNP) locus selected from a group consisting of;

rs993648, rs3924426, rs4799915, rs4933824, rs714881, and rs17054392; and

in the case that the individual'"'"'s genotype at the at least one SNP locus is associated with increased QT prolongation, predicting that the individual will experience above-average QT prolongation.

2. The method of claim 1, wherein the genotype associated with increased QT prolongation is selected from a group consisting of:

non-CT for rs993648, TT for rs3924426, non-CC for rs4799915, GG for rs4933824, non-GG for rs714881, and non-CT for rs17054392.

3. The method of claim 1, wherein the compound is an atypical antipsychotic.

4. The method of claim 3, wherein the atypical antipsychotic is selected from a group consisting of:

iloperidone, clozapine, risperidone, olanzapine, quetiapine, siprasidone, aripiprazole, paliperidone, asenapine, sertindole, zotepine, amisulpride, bifeprunox, melperone, pharmaceutically-acceptable salts thereof, metabolites thereof, and pharmaceutically-acceptable salts of metabolites thereof.

5. The method of claim 4, wherein the atypical antipsychotic is selected from a group consisting of:

iloperidone, an iloperidone metabolite, a pharmaceutically-acceptable salt of iloperidone, and a pharmaceutically-acceptable salt of an iloperidone metabolite.

6. The method of claim 5, wherein the iloperidone metabolite is selected from a group consisting of:

4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-α

-methylbenzene methanol, 1-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-hydroxyphenyl]ethanone, 1-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]-2-hydroxyethanone, 4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-hydroxy-α

-methylbenzene methanol, 4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-2-hydroxy-5-methoxy-α

-methylbenzene methanol, 1-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-2-hydroxy-5-methoxyphenyl]ethanone, and 1-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-2,5-dihydroxyphenyl]ethanone.

7. The method of claim 3, wherein the atypical antipsychotic is selected from a group consisting of:

iloperidone and 4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-α

-methylbenzene methanol.

8. A method of predicting an individual'"'"'s QT prolongation following administration of a compound capable of prolonging the individual'"'"'s QT interval, the method comprising:

determining the individual'"'"'s genotype at least one single nucleotide polymorphism (SNP) locus selected from a group consisting of;

rs993648, rs3924426, rs4799915, rs4933824, rs714881, and rs17054392; and

in the case that the individual'"'"'s genotype at the at least one SNP locus is associated with decreased QT prolongation, predicting that the individual will experience below-average QT prolongation.

9. The method of claim 8, wherein the genotype associated with decreased QT prolongation is selected from a group consisting of:

CT for rs993648, non-TT for rs3924426, CC for rs4799915, non-GG for rs4933824, GG for rs714881, and CT for rs17054392.

10. The method of claim 8, wherein the compound is an atypical antipsychotic.

11. The method of claim 10, wherein the atypical antipsychotic is selected from a group consisting of:

iloperidone, clozapine, risperidone, olanzapine, quetiapine, siprasidone, aripiprazole, paliperidone, asenapine, sertindole, zotepine, amisulpride, bifeprunox, melperone, pharmaceutically-acceptable salts thereof, metabolites thereof, and pharmaceutically-acceptable salts of metabolites thereof.

12. The method of claim 11, wherein the atypical antipsychotic is selected from a group consisting of:

iloperidone, an iloperidone metabolite, a pharmaceutically-acceptable salt of iloperidone, and a pharmaceutically-acceptable salt of an iloperidone metabolite.

13. The method of claim 12, wherein the iloperidone metabolite is selected from a group consisting of:

4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-α

-methylbenzene methanol, 1-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-hydroxyphenyl]ethanone, 1-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]-2-hydroxyethanone, 4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-hydroxy-α

-methylbenzene methanol, 4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxyl-2-hydroxy-5-methoxy-α

-methylbenzene methanol, 1-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-2-hydroxy-5-methoxyphenyl]ethanone, and 1-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-2,5-dihydroxyphenyl]ethanone.

14. The method of claim 10, wherein the atypical antipsychotic is selected from a group consisting of:

iloperidone and 4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-α

-methylbenzene methanol.

15. A method of treating a patient for one or more symptoms of a psychotic disorder, the method comprising:

determining the patient'"'"'s genotype in both copies of at least one single nucleotide polymorphism (SNP) locus selected from a group consisting of;

rs993648, rs3924426, rs4799915, rs4933824, rs714881, and rs17054392; and

treating the patient based upon whether the patient'"'"'s genotype at the at least one SNP locus is associated with increased QT prolongation.

16. The method of claim 15, wherein the genotype associated with increased QT prolongation is selected from a group consisting of:

non-CT for rs993648, TT for rs3924426, non-CC for rs4799915, GG for rs4933824, non-GG for rs714881, and non-CT for rs17054392.

17. The method of claim 15, wherein, in the case that the patient has a genotype associated with increased QT prolongation, treating the patient includes administering to the patient an effective amount of an atypical antipsychotic, the effective amount being less than would be administered to an individual that does not have a genotype associated with increased QT prolongation.

18. The method of claim 17, wherein the atypical antipyschotic is selected form a group consisting of:

iloperidone, clozapine, risperidone, olanzapine, quetiapine, siprasidone, aripiprazole, paliperidone, asenapine, sertindole, zotepine, amisulpride, bifeprunox, melperone, pharmaceutically-acceptable salts thereof, metabolites thereof, and pharmaceutically-acceptable salts of metabolites thereof.

19. The method of claim 17, wherein the atypical antipsychotic is selected from a group consisting of:

iloperidone, an iloperidone metabolite, a pharmaceutically-acceptable salt of iloperidone, and a pharmaceutically-acceptable salt of an iloperidone metabolite.

20. The method of claim 19, wherein the iloperidone metabolite is selected from a group consisting of:

4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-α

-methylbenzene methanol, 1-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-hydroxyphenyl]ethanone, 1-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]-2-hydroxyethanone, 4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-hydroxy-α

-methylbenzene methanol, 4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxyl-2-hydroxy-5-methoxy-α

-methylbenzene methanol, 1-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-2-hydroxy-5-methoxyphenyl]ethanone, and 1-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-2,5-dihydroxyphenyl]ethanone.

21. The method of claim 17, wherein the atypical antipsychotic is selected from a group consisting of:

iloperidone and 4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-α

-methylbenzene methanol.

22. The method of claim 17, wherein the effective amount is between about 2 mg/day and about 24 mg/day.

23. The method of claim 22, wherein the effective amount is between about 5 mg/day and about 20 mg/day.

24. The method of claim 23, wherein the effective amount is between about 10 mg/day and about 15 mg/day.

25. The method of claim 15, wherein, in the case that the patient does not have a genotype associated with increased QT prolongation, treating the patient includes administering to the patient an effective amount of an atypical antipsychotic, the effective amount being more than would be administered to an individual that has a genotype associated with increased QT prolongation.

26. The method of claim 25, wherein the atypical antipyschotic is selected form a group consisting of:

iloperidone, clozapine, risperidone, olanzapine, quetiapine, siprasidone, aripiprazole, paliperidone, asenapine, sertindole, zotepine, amisulpride, bifeprunox, melperone, pharmaceutically-acceptable salts thereof, metabolites thereof, and pharmaceutically-acceptable salts of metabolites thereof.

27. The method of claim 25, wherein the atypical antipsychotic is selected from a group consisting of:

iloperidone, an iloperidone metabolite, a pharmaceutically-acceptable salt of iloperidone, and a pharmaceutically-acceptable salt of an iloperidone metabolite.

28. The method of claim 27, wherein the iloperidone metabolite is selected from a group consisting of:

4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-α

-methylbenzene methanol, 1-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-hydroxyphenyl]ethanone, 1-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]-2-hydroxyethanone, 4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-hydroxy-α

-methylbenzene methanol, 4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxyl-2-hydroxy-5-methoxy-α

-methylbenzene methanol, 1-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-2-hydroxy-5-methoxyphenyl]ethanone, and 1-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-2,5-dihydroxyphenyl]ethanone.

29. The method of claim 25, wherein the atypical antipsychotic is selected from a group consisting of:

iloperidone and 4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-α

-methylbenzene methanol.

30. The method of claim 25, wherein the effective amount is between about 24 mg/day and about 50 mg/day.

31. The method of claim 30, wherein the effective amount is between about 30 mg/day and about 50 mg/day.

32. The method of claim 31, wherein the effective amount is between about 40 mg/day and about 50 mg/day.

33. The method of claim 15, wherein, in the case that the patient has genotypes associated with increased QT prolongation at two or more of the SNP loci, the effective amount is less than would be administered to an individual having only one genotype associated with increased QT prolongation.

34. The method of claim 15, wherein, in the case that the patient has genotypes associated with increased QT prolongation at three or more of the SNP loci, the effective amount is less than would be administered to an individual having two or fewer genotypes associated with increased QT prolongation.

35. The method of claim 15, wherein, in the case that the patient has genotypes associated with increased QT prolongation at four or more of the SNP loci, the effective amount is less than would be administered to an individual having three or fewer genotypes associated with increased QT prolongation.

36. The method of claim 15, wherein, in the case that the patient has genotypes associated with increased QT prolongation at five or more of the SNP loci, the effective amount is less than would be administered to an individual having four or fewer genotypes associated with increased QT prolongation.

37. The method of claim 15, wherein, in the case that the patient has genotypes associated with increased QT prolongation at six of the SNP loci, the effective amount is less than would be administered to an individual having five or fewer genotypes associated with increased QT prolongation.

38. The method of claim 15, wherein treating the patient includes not administering an atypical antipsychotic to the patient.

39. The method of claim 15, wherein treating the patient includes monitoring the patient for QT prolongation.

40. A method of administering to an individual a compound capable of prolonging the individual'"'"'s QT interval, the method comprising:

determining at least a portion of an individual'"'"'s ceramide kinase-like (CERKL) gene sequence; and

in the case that a portion of the individual'"'"'s CERKL gene sequence is associated with an increased risk of QT prolongation, performing at least one of the following;

administering to the individual a quantity of the compound less than would be administered to an individual having a CERKL gene sequence not associated with an increased risk of QT prolongation,

administering to the individual a quantity of the compound equal to that which would be administered to an individual having a CERKL gene sequence not associated with an increased risk of QT prolongation;

or

monitoring the patient for QT prolongation;

or

electing instead to treat the individual with a different compound not known to be associated with QT prolongation.

41. The method of claim 40, wherein the portion of the individual'"'"'s CERKL gene sequence includes the rs993648 single nucleotide polymorphism (SNP).

42. The method of claim 41, wherein the gene sequence associated with an increased risk of QT prolongation includes a TT or a CT genotype at the rs993648 SNP.

43. The method of claim 40, wherein the compound is an atypical antipsychotic.

44. The method of claim 43, wherein the atypical antipsychotic is selected from a group consisting of:

iloperidone, clozapine, risperidone, olanzapine, quetiapine, siprasidone, aripiprazole, paliperidone, asenapine, sertindole, zotepine, amisulpride, bifeprunox, melperone, pharmaceutically-acceptable salts thereof, metabolites thereof, and pharmaceutically-acceptable salts of metabolites thereof.

45. The method of claim 43, wherein the atypical antipsychotic is selected from a group consisting of:

iloperidone, an iloperidone metabolite, a pharmaceutically-acceptable salt of iloperidone, and a pharmaceutically-acceptable salt of an iloperidone metabolite.

46. The method of claim 45, wherein the iloperidone metabolite is selected from a group consisting of:

4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-α

-methylbenzene methanol, 1-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-hydroxyphenyl]ethanone, 1-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]-2-hydroxyethanone, 4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-hydroxy-α

-methylbenzene methanol, 4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-2-hydroxy-5-methoxy-α

-methylbenzene methanol, 1-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-2-hydroxy-5-methoxyphenyl]ethanone, and 1-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-2,5-dihydroxyphenyl]ethanone.

47. The method of claim 43, wherein the atypical antipsychotic is selected from a group consisting of:

iloperidone and 4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-α

-methylbenzene methanol.

48. A kit for use in determining treatment strategy for a patient with a psychotic disorder, schizophrenia, or bipolar disorder comprising:

at least one polynucleotide able to recognize and bind to a portion of DNA containing a single nucleotide polymorphism (SNP) selected from a group consisting of;

rs993648, rs3924426, rs4799915, rs4933824, rs714881, and rs17054392;

a container suitable for containing the at least one polynucleotide and a sample of chromosomal DNA from the said individual wherein the at least one polynucleotide can contact the chromosomal DNA; and

means to detect the combination of the at least one polynucleotide with the chromosomal DNA and thereby to ascertain what the genotype of the individual is at the SNP.

49. The kit of claim 48, including at least one polynucleotide able to recognize and bind to a portion of DNA containing each of the rs993648, rs3924426, rs4799915, rs4933824, rs714881, and rs17054392 SNPs.

50. Iloperidone, an active metabolite of iloperidone, or a salt of iloperidone or of an active metabolite of iloperidone for use in the treatment of patients suffering from one or more symptoms of a psychotic disorder, schizophrenia, or bipolar disorder in a patient that has a genotype that is associated with increased QT prolongation at least one of the SNP locus selected from a group consisting of:

rs993648, rs3924426, rs4799915, rs4933824, rs714881, and rs17054392 SNPs.