METHODS FOR THE ADMINISTRATION OF ILOPERIDONE

• US 20100063093A1
• Filed: 09/10/2008
• Published: 03/11/2010
• Est. Priority Date: 03/28/2007
• Status: Abandoned Application

• Current Assignee: Vanda Pharmaceuticals Incorporated
• Original Assignee: Vanda Pharmaceuticals Incorporated
• Inventors: Polymeropoulos, Mihael, Volpi, Simona, Lavedan, Christian, Wolfgang, Curt
• Application Number:
  US12/208,027
• Publication Number:
  US 20100063093A1
• Time in Patent Office: Days
• US Class Current: 514/321
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/135 having aromatic rings , e.g. ketamine, nortriptyline methadone A61K31/137
• CPC Class Codes: A61K 31/4525 containing a five-membered ring with oxygen as a ring hetero atom
• CPC Class Codes: A61K 31/454 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/22 Anxiolytics
• 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 methods for the identification of genetic polymorphisms that may be associated with a risk for QT prolongation after treatment with iloperidone and related methods of administering iloperidone to patients with such polymorphisms.

Claims

1. A method for treating a patient with an active pharmaceutical ingredient including at least one of:

iloperidone, a pharmaceutically acceptable salt of iloperidone, an active metabolite of iloperidone, and a pharmaceutically acceptable salt of an active metabolite of iloperidone, comprising the steps of;

determining the patient'"'"'s CYP2D6 genotype; and

administering to the patient an effective amount of the active pharmaceutical ingredient, whereby the amount of the active pharmaceutical ingredient is determined based on the patient'"'"'s CYP2D6 genotype.

2. The method of claim 1, wherein the amount of the active pharmaceutical ingredient is decreased if the genotype indicates decreased enzymatic activity of the CYP2D6 enzyme relative to the wild type.

3. The method of claim 2, wherein the amount of the active pharmaceutical ingredient is decreased if the patient'"'"'s CYP2D6G1846A genotype is AA.

4. The method of claim 2, wherein the amount of the active pharmaceutical ingredient is decreased if the patient'"'"'s CYP2D6G1846A genotype is GA.

5. The method of claim 2, wherein the amount of the active pharmaceutical ingredient is decreased if the patient'"'"'s CYP2D6C100T genotype is TT.

6. The method of claim 2, wherein the amount of the active pharmaceutical ingredient is decreased if the patient'"'"'s CYP2D6C100T genotype is CT.

7. The method of claim 2, wherein the amount of the active pharmaceutical ingredient is decreased if the patient'"'"'s CYP2D6 genotype is 100C>

T;

1661G>

C;

1846G>

A.

8. The method of claim 2, wherein the amount of the active pharmaceutical ingredient is decreased if the patient'"'"'s CYPD26 genotype is 100C>

T;

1661G>

C;

4180G>

C.

9. The method of claim 2, wherein the amount of the active pharmaceutical ingredient is decreased if the patient'"'"'s CYP2D6 genotype is CYP2D6 deleted.

10. The method of claim 2, wherein the amount of the active pharmaceutical ingredient is decreased if the patient'"'"'s CYP2D6 genotype is −

1584C;

−

1235 A>

G;

−

740 C>

T;

−

678 G>

A;

CYP2D7 gene conversion in intron 1;

1661 G>

C;

2850 C>

T;

2988 G>

A;

4180 G>

C.

11. The method of claim 1, wherein the patient is suffering from at least one of schizophrenia, schizoaffective disorder, depression, bipolar mania/depression, cardiac arrythmia, Tourette'"'"'s Syndrome, a psychotic disorder, a delusional disorder, and schizophreniform disorder.

12. The method of claim 11, wherein the patient is at risk for a prolonged QT interval.

13. A method for treating a patient who is a CYP2D6 poor metabolizer with a pharmaceutically active ingredient including at least one of:

iloperidone, a pharmaceutically acceptable salt of iloperidone, an active metabolite of iloperidone, and a pharmaceutically acceptable salt of an active metabolite of iloperidone, wherein the patient is administered a lower dosage than would be given to an individual who is not a CYP2D6 poor metabolizer.

14. The method of claim 13, wherein the patient is determined to be a CYP2D6 poor metabolizer based on at least one of the patient'"'"'s genotype, the patient'"'"'s phenotype, and the fact that the patient is being treated with an agent that reduces CYP2D6 activity.

15. The method of claim 13, wherein the patient'"'"'s genotype includes at least one CYP2D6 allele selected from a group consisting of 2549 A deletion, 1846 G>

A, 1707 T deletion, 2935 A>

C, 1758 G>

T, 2613-2615 AGA deletion, 1023 C>

T, 2850 C>

T, 4180G>

C, 1659 G>

A, 1661 G>

C, 2850 C>

T, 3183 G>

A, −

1584 C, −

1235 A>

G, −

740C>

T, −

678 G>

A, 100 C>

T, 2988 G>

A, and CYP2D6 deletion

16. The method of claim 14, wherein the patient'"'"'s genotype includes at least one deletion of the CYP2D6 gene.

17. The method of claim 15, wherein the patient'"'"'s genotype includes a CYP2D7gene conversion in intron 1.

18. The method of claim 13, wherein the patient is suffering from at least one of schizophrenia, schizoaffective disorder, depression, bipolar mania/depression, cardiac arrythmia, Tourette'"'"'s Syndrome, a psychotic disorder, a delusional disorder, and schizophreniform disorder.

19. A method of treating a patient with a pharmaceutically active ingredient including at least one of:

iloperidone, a pharmaceutically acceptable salt of iloperidone, an active metabolite of iloperidone, and a pharmaceutically acceptable salt of an active metabolite of iloperidone comprising the steps of;

determining whether the patient is being administered a CYP2D6 inhibitor; and

reducing the dosage of drug if the patient is being administered a CYP2D6 inhibitor.

20. The method of claim 19, wherein the CYP2D6 inhibitor includes at least one of paroxetine, dolasetron, venlafaxin, and fluoxetine.

21. The method of claim 19, wherein the patient is suffering from at least one of schizophrenia, schizoaffective disorder, depression, bipolar mania/depression, cardiac arrythmia, Tourette'"'"'s Syndrome, a psychotic disorder, a delusional disorder, and schizophreniform disorder.

22. A method for determining a patient'"'"'s CYP2D6 phenotype comprising the steps of:

administering to the patient a quantity of at least one of;

iloperidone, a pharmaceutically acceptable salt of iloperidone, an active metabolite of iloperidone, and a pharmaceutically acceptable salt of an active metabolite of iloperidone; and

determining a first concentration of at least one of iloperidone and an iloperidone metabolite in the patient'"'"'s blood.

23. The method of claim 22, wherein the iloperidone metabolite is selected from a group consisting of P88 and P95.

24. The method of claim 23, wherein a first concentration is determined for each of P88 and P95.

25. The method of claim 24, wherein the patient is designated a poor metabolizer if the ratio of first concentrations of P88 to P95 is greater than or equal to about 2.0.

26. The method of claim 24, wherein the patient is designated a poor metabolizer if the ratio of first concentrations of (P88+iloperidone)/P95 is greater than or equal to about 1.0.

27. The method of claim 24, wherein the patient is designated a poor metabolizer if the ratio of first concentrations of iloperidone and P88 to P95 is greater than or equal to about 3.0.

28. The method of claim 22, further comprising the steps of:

administering to the patient at least one CYP2D6 inhibitor;

determining a second concentration of at least one of iloperidone and an iloperidone metabolite in the patient'"'"'s blood; and

comparing the first and second concentrations.

29. The method of claim 28, wherein the CYP2D6 inhibitor is selected from a group consisting of paroxetine, ketoconazole, and fluoxetine.

30. The method of claim 28, wherein a second concentration is determined for each of P88 and P95.

31. The method of claim 30, wherein the patient is designated a poor metabolizer if the ratio of second concentrations of P88 to P95 is greater than or equal to about 2.0.

32. The method of claim 28, wherein a first and second concentration is determined for each of iloperidone, P88, and P95.

33. The method of claim 32, wherein the patient is designated a poor metabolizer if the ratio of second concentrations of iloperidone and P88 to P95 is greater than or equal to about 3.0.

34. A method for determining whether a patient is at risk for prolongation of his or her QTc interval due to administration of at least one of:

iloperidone, a pharmaceutically acceptable salt of iloperidone, an active metabolite of iloperidone, and a pharmaceutically acceptable salt of an active metabolite of iloperidone comprising the steps of;

measuring a first QTc interval;

administering to the patient a quantity of at least one of;

iloperidone, a pharmaceutically acceptable salt of iloperidone, an active metabolite of iloperidone, and a pharmaceutically acceptable salt of an active metabolite of iloperidone

measuring a second QTc interval; and

comparing the first and second QTc interval.

35. The method of claim 34, wherein the dose of iloperidone administered to the patient is about 24 milligrams per day.

36. The method of claim 34, further comprising the step of administering to the patient at least one CYP2D6 inhibitor after the administering step.

37. The method of claim 36, wherein the CYP2D6 inhibitor is selected from a group consisting of paroxetine, ketoconazole, and fluoxetine