METHODS FOR THE ADMINISTRATION OF ILOPERIDONE
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.
1 . A method for treating a patient with iloperidone, wherein the patient is suffering from schizophrenia, the method comprising the steps of:
determining whether the patient demonstrates reduced CYP2D6-mediated metabolism relative to wild type by:
obtaining or having obtained a biological sample from the patient; and
performing or having performed a genotyping assay on the biological sample to determine if the patient has a genotype associated with reduced CYP2D6-mediated metabolism; and
if the patient has a CYP2D6 normal metabolizer genotype, then internally administering iloperidone to the patient in a first amount, and
if the patient has a CYP2D6 poor metabolizer genotype, then internally administering iloperidone to the patient in a second amount,
wherein the first amount of iloperidone causes an iloperidone blood exposure level that is therapeutically effective in a patient having a CYP2D6 normal metabolizer genotype,
wherein the second amount of iloperidone is one of 25%, 50%, or 75% of the first amount, and
wherein a risk of QTc prolongation for a patient having a CYP2D6 poor metabolizer genotype is lower following the internal administration of the second amount of iloperidone than it would be if the iloperidone were administered in the first amount.
2 . The method of claim 1 , wherein the performing or having performed the genotyping assay step comprises:
extracting or having extracted genomic DNA or mRNA from the biological sample, and
sequencing or having sequenced CYP2D6 DNA derived from the extracted genomic DNA or from the extracted mRNA,
wherein the sequencing or having sequenced step further comprises: amplifying or having amplified a CYP2D6 region in the extracted genomic DNA or mRNA to prepare a DNA sample enriched in DNA from the CYP2D6 gene region; and
sequencing or having sequenced the DNA sample by hybridizing the DNA sample to nucleic acid probes to determine if the patient has a genotype associated with reduced CYP2D6-mediated metabolism.
3 . The method of claim 1 , wherein the CYP2D6 poor metabolizer genotype includes two alleles, wherein each of the two alleles is one of the following: *3, *4, *5, *6, *7, *8, *9, *10, *17, or *41, and wherein the second amount is 50% of the first amount.
4 . The method of claim 1 , further comprising, if the patient has a CYP2D6 intermediate metabolizer genotype, then internally administering iloperidone to the patient in a third amount,
wherein the third amount is greater than the second amount, and smaller than the first amount, and
wherein a risk of QTc prolongation for a patient having a CYP2D6 intermediate metabolizer genotype is lower following the internal administration of the third amount of iloperidone than it would be if the iloperidone were administered in the first amount.
5 . The method of claim 4 , wherein the CYP2D6 intermediate metabolizer genotype includes two alleles, wherein one of the two alleles is one of the following: *3, *4, *5, *6, *7, *8, *9, *10, *17, or *41,
wherein the other of the two alleles is one of *1 or *2.
6 . The method of claim 1 , wherein the first amount of iloperidone is about 24 mg/day, and the second amount of iloperidone is about 12 mg/day.
7 . The method of claim 4 , wherein the first amount of iloperidone is about 24 mg/day, the second amount of iloperidone is about 12 mg/day, and the third amount of iloperidone is at least 12 mg/day and smaller than 24 mg/day.
7 . The method of claim 6 , wherein the first amount of iloperidone is provided in an amount of 12 mg b.i.d., and wherein the second amount of iloperidone is 6 mg b.i.d.
8 . The method of claim 1 , wherein the first amount of iloperidone and the second amount of iloperidone are provided in a controlled release depot formulation of iloperidone.
9 . The method of claim 8 , wherein the first amount of iloperidone is up to 1000 mg, and wherein the second amount of iloperidone is up to 500 mg.
10 . A method of treating a patient who is suffering from a schizoaffective disorder, depression, Tourette's syndrome, a psychotic disorder or a delusional disorder, the method comprising:
determining if the patient has a genotype associated with reduced CYP2D6-mediated metabolism by obtaining or having obtained a biological sample from the patient, and performing or having performed a genotyping assay on the biological sample to determine whether the patient has a genotype associated with reduced CYP2D6-mediated metabolism, and
if the patient has a CYP2D6 normal metabolizer genotype, then internally administering iloperidone to the patient in a first amount, and
if the patient has a CYP2D6 poor metabolizer genotype, then internally administering iloperidone to the patient in a second amount,
wherein the first amount of iloperidone causes an iloperidone blood exposure level that is therapeutically effective in a patient having a CYP2D6 normal metabolizer genotype, and
wherein the second amount of iloperidone is one of 25%, 50%, or 75% of first amount.
11 . The method of claim 10 , wherein the patient is at risk for a prolonged QT interval.
12 . The method of claim 10 , wherein the CYP2D6 poor metabolizer genotype includes two alleles, wherein each of the two alleles is one of the following: *3, *4, *5, *6, *7, *8, *9, *10, *17, or *41, and wherein the second amount is 50% of the first amount.
13 . The method of claim 10 , further comprising, if the patient has a CYP2D6 intermediate metabolizer genotype, then internally administering iloperidone to the patient in a third amount,
wherein the third amount is greater than the second amount, and smaller than the first amount, and
wherein a risk of QTc prolongation for a patient having a CYP2D6 intermediate metabolizer genotype is lower following the internal administration of the third amount of iloperidone than it would be if the iloperidone were administered in the first amount.
14 . The method of claim 13 , wherein the CYP2D6 intermediate metabolizer genotype includes two alleles, wherein one of the two alleles is one of the following: *3, *4, *5, *6, *7, *8, *9, *10, *17, or *41,
wherein the other of the two alleles is one of *1 or *2.
15 . The method of claim 10 , wherein the first amount of iloperidone is about 24 mg/day, and the second amount of iloperidone is 12 mg/day.
16 . The method of claim 10 , wherein the first amount of iloperidone is a controlled release depot formulation of iloperidone including an amount of iloperidone of up to 1000 mg, and
wherein the second amount of iloperidone is a controlled release depot formulation of iloperidone including an amount of iloperidone of up to about 500 mg.
17 . A method of treating a patient who is suffering from a schizoaffective disorder, depression, Tourette's syndrome, a psychotic disorder or a delusional disorder, the method comprising:
determining if the patient is at risk for iloperidone-induced QTc prolongation by obtaining or having obtained a biological sample from the patient, and performing or having performed a genotyping assay on the biological sample to determine whether the patient has a CYP2D6 poor metabolizer genotype, wherein the presence of a CYP2D6 poor metabolizer genotype indicates risk for iloperidone-induced QTc prolongation, and
if the patient is not at risk for iloperidone-induced QTc prolongation, then internally administering iloperidone to the patient in a first amount, and
if the patient is at risk for iloperidone-induced QTc prolongation, then internally administering iloperidone to the patient in a second amount,
wherein the first amount of iloperidone causes an iloperidone blood exposure level that is therapeutically effective in a patient not having a CYP2D6 poor metabolizer genotype, and
wherein the second amount of iloperidone is one of 25%, 50%, or 75% of first amount.
17 . The method of claim 16 , wherein the patient is at risk for iloperidone-induced QTc prolongation, and is a CYP2D6 poor metabolizer.
18 . The method of claim 17 , wherein the patient is a CYP2D6 poor metabolizer having a CYP2D6 genotype including two alleles, wherein each of the two alleles is one of the following: *3, *4, *5, *6, *7, *8, *9, *10, *17, or *41.
19 . The method of claim 16 , wherein the first amount of iloperidone is a controlled release depot formulation of iloperidone including an amount of iloperidone of up to about 1000 mg, and
wherein the second amount of iloperidone is a controlled release depot formulation of iloperidone including an amount of iloperidone of up to about 500 mg.
20 . The method of claim 16 , wherein the method comprises: wherein the first amount of iloperidone is about 24 mg/day, and the second amount of iloperidone is about 12 mg/day.