Methods for the Administration of Certain VMAT2 Inhibitors
Provided are methods of administering a vesicular monoamine transport 2 (VMAT2) inhibitor chosen from valbenazine and (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol, or a pharmaceutically acceptable salt and/or isotopic variant thereof to a patient in need thereof wherein the patient is being treated with a strong cytochrome P450 3A4 (CYP3A4) inducer.
1 - 78 . (canceled)
79 . A method of ameliorating one or more symptoms of a neurological or psychiatric disease or disorder in a patient, wherein the patient is also being administered a strong cytochrome P450 3A4 (CYP3A4) inducer, comprising:
discontinuing the administration of the strong CYP3A4 inducer, and then
orally administering to the patient a vesicular monoamine transporter 2 (VMAT2) inhibitor chosen from (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester and a pharmaceutically acceptable salt thereof, thereby avoiding the concomitant use of the VMAT2 inhibitor with the strong CYP3A4 inducer.
80 . The method of claim 79 , wherein the strong CYP3A4 inducer is chosen from nevirapine, pentobarbital, phenytoin, lumacaftor, rifabutin, rifampin, carbamazepine, fosphenytoin, phenobarbital, primidone, enzalutamide, mitotane, and St. John's Wort.
81 . The method of claim 79 , wherein the strong CYP3A4 inducer is chosen from rifampin, carbamazepine, phenytoin, and St. John's Wort.
82 . The method of claim 79 , wherein the strong CYP3A4 inducer is rifampin.
83 . The method of claim 79 , wherein the VMAT2 inhibitor is administered in the form of a capsule.
84 . The method of claim 79 , wherein the neurological or psychiatric disease or disorder is a hyperkinetic movement disorder.
85 . The method of claim 84 , wherein the hyperkinetic movement disorder is tardive dyskinesia.
86 . The method of claim 84 , wherein the hyperkinetic movement disorder is chorea.
87 . The method of claim 86 , wherein the hyperkinetic movement disorder is chorea associated with Huntington's disease.
88 . The method of claim 79 , wherein the VMAT2 inhibitor is a pharmaceutically acceptable salt of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester.
89 . The method of claim 79 , wherein the VMAT2 inhibitor is a ditosylate salt of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester.
90 . The method of claim 79 , wherein the ditosylate salt of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester is in polymorphic Form I.
91 . The method of claim 79 , wherein the therapeutically effective amount is an amount equivalent to about 40 mg as measured by (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester free base once daily for one week, and an amount equivalent to about 80 mg as measured by (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester free base once daily after one week.
92 . The method of claim 79 , wherein the therapeutically effective amount is an amount equivalent to about 40 mg as measured by (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester free base once daily.
93 . The method of claim 79 , wherein the therapeutically effective amount is an amount equivalent to about 60 mg as measured by (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester free base once daily.
94 . The method of claim 79 , wherein the therapeutically effective amount is an amount equivalent to about 80 mg as measured by (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester free base once daily.
95 . A method of ameliorating one or more symptoms of a neurological or psychiatric disease or disorder in a patient, comprising:
(a) orally administering to the patient a therapeutically effective amount of a vesicular monoamine transporter 2 (VMAT2) inhibitor chosen from (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester and a pharmaceutically acceptable salt thereof;
(b) subsequently determining that the patient is being administered a strong cytochrome P450 3A4 (CYP3A4) inducer;
(c) discontinuing the administration of the strong CYP3A4 inducer; and
(d) continuing the administration of the VMAT2 inhibitor.
96 . The method of claim 95 , wherein the strong CYP3A4 inducer is chosen from rifampin, carbamazepine, phenytoin, and St. John's Wort.
97 . The method of claim 95 , wherein the strong CYP3A4 inducer is rifampin.
98 . The method of claim 95 , wherein the neurological or psychiatric disease or disorder is a hyperkinetic movement disorder.
99 . The method of claim 98 , wherein the hyperkinetic movement disorder is tardive dyskinesia.
100 . The method of claim 98 , wherein the hyperkinetic movement disorder is chorea.
101 . The method of claim 100 , wherein the hyperkinetic movement disorder is chorea associated with Huntington's disease.
102 . The method of claim 95 , wherein the VMAT2 inhibitor is a pharmaceutically acceptable salt of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester.
103 . The method of claim 102 , wherein the VMAT2 inhibitor is a ditosylate salt of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester.
104 . The method of claim 95 , wherein the therapeutically effective amount is an amount equivalent to about 40 mg as measured by (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester free base once daily for one week, and an amount equivalent to about 80 mg as measured by (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester free base once daily after one week.
105 . The method of claim 95 , wherein the therapeutically effective amount is an amount equivalent to about 40 mg as measured by (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester free base once daily.
106 . The method of claim 95 , wherein the therapeutically effective amount is an amount equivalent to about 60 mg as measured by (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester free base once daily.
107 . The method of claim 95 , wherein the therapeutically effective amount is an amount equivalent to about 80 mg as measured by (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester free base once daily.
108 . A method of ameliorating one or more symptoms of a neurological or psychiatric disease or disorder in a patient, wherein the patient is being administered a strong cytochrome P450 3A4 (CYP3A4) inducer, comprising:
discontinuing the administration of the strong CYP3A4 inducer; and then
orally administering once daily to the patient a vesicular monoamine transporter 2 (VMAT2) inhibitor, which is a ditosylate salt of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester, in an amount equivalent to about 40 mg as measured by (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester free base for one week, and an amount equivalent to about 80 mg as measured by (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester free base after one week, thereby avoiding the concomitant use of the VMAT2 inhibitor with the strong CYP3A4 inducer; and
wherein the patient has not been administered the VMAT 2 inhibitor prior to the discontinuation of the strong CYP3A4 inducer.
109 . The method of claim 108 , wherein the neurological or psychiatric disease or disorder is a hyperkinetic movement disorder.
110 . The method of claim 109 , wherein the hyperkinetic movement disorder is tardive dyskinesia.
111 . The method of claim 109 , wherein the hyperkinetic movement disorder is chorea.
112 . The method of claim 111 , wherein the hyperkinetic movement disorder is chorea associated with Huntington's disease.
113 . A method of ameliorating one or more symptoms of a neurological or psychiatric disease or disorder in a patient, wherein the patient is being administered a strong cytochrome P450 3A4 (CYP3A4) inducer, comprising:
discontinuing the administration of the strong CYP3A4 inducer; and then
orally administering once daily to the patient a vesicular monoamine transporter 2 (VMAT2) inhibitor, which is a ditosylate salt of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester, in an amount chosen from about 40 mg, about 60 mg, and about 80 mg as measured by (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester free base, thereby avoiding the concomitant use of the VMAT2 inhibitor with the strong CYP3A4 inducer; and
wherein the patient has not been administered the VMAT 2 inhibitor prior to the discontinuation of the strong CYP3A4 inducer.
114 . The method of claim 113 , wherein the neurological or psychiatric disease or disorder is a hyperkinetic movement disorder.
115 . The method of claim 114 , wherein the hyperkinetic movement disorder is tardive dyskinesia.
116 . The method of claim 114 , wherein the hyperkinetic movement disorder is chorea.
117 . The method of claim 116 , wherein the hyperkinetic movement disorder is chorea associated with Huntington's disease.
118 . A method of ameliorating one or more symptoms of a neurological or psychiatric disease or disorder in a patient, comprising:
(a) orally administering once daily to the patient a therapeutically effective amount of a vesicular monoamine transporter 2 (VMAT2) inhibitor, which is a ditosylate salt of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester, in an amount chosen from about 40 mg, about 60 mg, and about 80 mg as measured by (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester free base;
(b) subsequently determining that the patient is being administered a strong cytochrome P450 3A4 (CYP3A4) inducer;
(c) discontinuing the administration of the strong CYP3A4 inducer; and
(d) continuing the administration of the VMAT2 inhibitor, thereby avoiding the concomitant use of the VMAT2 inhibitor with the strong CYP3A4 inducer.
119 . The method of claim 118 , wherein the neurological or psychiatric disease or disorder is a hyperkinetic movement disorder.
120 . The method of claim 119 , wherein the hyperkinetic movement disorder is tardive dyskinesia.
121 . The method of claim 119 , wherein the hyperkinetic movement disorder is chorea.
122 . The method of claim 121 , wherein the hyperkinetic movement disorder is chorea associated with Huntington's disease.