US2010063093A1PendingUtilityA1

Methods for the administration of iloperidone

64
Assignee: WOLFGANG CURTPriority: Mar 28, 2007Filed: Sep 10, 2008Published: Mar 11, 2010
Est. expiryMar 28, 2027(~0.7 yrs left)· nominal 20-yr term from priority
Inventors:Curt D. WolfgangMihael H. PolymeropoulosChristian LavedanSimona Volpi
A61P 9/06A61P 25/18A61P 25/22A61P 25/24A61P 25/00C12Q 2600/106A61K 31/135A61K 31/4525A61K 31/496A61K 31/454C12Q 1/6883C12Q 2600/156
64
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Claims

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

exact text as granted — not AI-modified
What is claimed is: 
     
         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

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