Methods for the Administration of Certain VMAT2 Inhibitors

1 . A method 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 a cytochrome P450 2D6 (CYP2D6) poor metabolizer, comprising:

administering a therapeutically effective amount of the VMAT2 inhibitor to the patient who is a CYP2D6 poor metabolizer.

2 . The method of claim 1 , further comprising monitoring the patient for one or more exposure-related adverse reactions.

3 . The method of claim 1 or 2 , further comprising reducing the amount of the VMAT2 inhibitor based on the patient's ability to tolerate one or more exposure-related adverse reactions.

4 . A method 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, comprising:

administering to the patient a therapeutically effective amount of the VMAT2 inhibitor,

subsequently determining that the patient is a poor metabolizer of cytochrome P450 2D6 (CYP2D6), and

continuing administration of the therapeutically effective amount of the VMAT2 inhibitor to the patient.

5 . A method 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, comprising:

administering to the patient a therapeutically effective amount of the VMAT2 inhibitor,

subsequently determining that the patient is a poor metabolizer of cytochrome P450 2D6 (CYP2D6), and

administering to the patient a reduced amount of the VMAT2 inhibitor.

6 . The method of claim 4 or 5 , further comprising monitoring the patient for one or more exposure-related adverse reactions.

7 . The method of any one of claims 4 to 6 , further comprising reducing the amount of the VMAT2 inhibitor based on the patient's ability to tolerate one or more exposure-related adverse reactions.

8 . The method of any one of claims 1 to 7 , further comprising informing the patient or a medical care worker that administration of the VMAT2 inhibitor to a patient who is a CYP2D6 poor metabolizer may result in increased exposure of (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol.

9 . The method of any one of claims 1 to 8 , further comprising informing the patient or a medical care worker that administration of the VMAT2 inhibitor to a patient who is a CYP2D6 poor metabolizer may result in increased risk of one or more exposure-related adverse reactions.

10 . The method of any one of claims 1 to 9 , further comprising informing the patient or a medical care worker that administration of the VMAT2 inhibitor to a patient who is a CYP2D6 poor metabolizer may prolong the patient's QT interval.

11 . The method of claims 2 , 3 , or 6 to 10 , wherein the one or more exposure-related adverse reactions is chosen from somnolence, anticholinergic effects, balance disorders or falls, headache, akathisia, vomiting, nausea, arthralgia, QT prolongation, increase in blood glucose, increase in weight, respiratory infections, drooling, dyskinesia, extrapyramidal symptoms (non-akathisia), anxiety, insomnia, increase in prolactin, increase in alkaline phosphatase, and increase in bilirubin.

12 . The method of claim 11 , wherein the one or more exposure-related adverse reactions is chosen from somnolence, anticholinergic effects, balance disorders or falls, headache, akathisia, vomiting, nausea, arthralgia, and QT prolongation.

13 . The method of claim 12 , wherein the one or more exposure-related adverse reactions is chosen from somnolence and QT prolongation.

14 . The method of any one of claims 1 to 13 , wherein the therapeutically effective amount is less than the amount that is administered to a patient who is not a CYP2D6 poor metabolizer.

15 . The method of any one of claims 1 to 13 , wherein the therapeutically effective amount is the same amount as that administered to a patient who is not a CYP2D6 poor metabolizer.

16 . The method of any one of claims 1 to 15 , wherein the patient has a CYP2D6 poor metabolizer genotype.

17 . The method of claim 16 , wherein the CYP2D6 poor metabolizer genotype is chosen from the CYP2D6G1846A genotype or the CYP2D6C100T genotype.

18 . The method of claim 17 , wherein the CYP2D6 poor metabolizer genotype is one of the CYP2D6G1846A (AA) genotype or the CYP2D6G1846A (AG) genotype.

19 . The method of claim 18 , wherein the CYP2D6 poor metabolizer genotype is the CYP2D6G1846A (AA) genotype.

20 . The method of claim 17 , wherein the CYP2D6 poor metabolizer genotype is one of the CYP2D6C100T (TT) genotype or the CYP2D6C100T (CT) genotype.

21 . The method of claim 20 , wherein the CYP2D6 poor metabolizer genotype is the CYP2D6C100T (TT) genotype.

22 . The method of any one of claims 1 to 21 , wherein the VMAT2 inhibitor is administered to the patient to treat a neurological or psychiatric disease or disorder.

23 . The method of claim 22 , wherein the neurological or psychiatric disease or disorder is a hyperkinetic movement disorder, mood disorder, bipolar disorder, schizophrenia, schizoaffective disorder, mania in mood disorder, depression in mood disorder, treatment-refractory obsessive compulsive disorder, neurological dysfunction associated with Lesch-Nyhan syndrome, agitation associated with Alzheimer's disease, Fragile X syndrome or Fragile X-associated tremor-ataxia syndrome, autism spectrum disorder, Rett syndrome, or chorea-acanthocytosis.

24 . The method of claim 23 , wherein the neurological or psychiatric disease or disorder is a hyperkinetic movement disorder.

25 . The method of claim 24 , wherein the hyperkinetic movement disorder is tardive dyskinesia.

26 . The method of claim 24 , wherein the hyperkinetic movement disorder is Tourette's syndrome.

27 . The method of claim 24 , wherein the hyperkinetic movement disorder is Huntington's disease.

28 . The method of claim 24 , wherein the hyperkinetic movement disorder is tics.

29 . The method of claim 24 , wherein the hyperkinetic movement disorder is chorea associated with Huntington's disease.

30 . The method of claim 24 , wherein the hyperkinetic movement disorder is ataxia, chorea, dystonia, Huntington's disease, myoclonus, restless leg syndrome, or tremors.

31 . The method of any one of claims 1 to 30 , wherein the VMAT2 inhibitor is administered orally.

32 . The method of any one of claims 1 to 31 , wherein the VMAT2 inhibitor is administered in the form of a tablet or capsule.

33 . The method of any one of claims 1 to 32 , wherein the VMAT2 inhibitor is administered with or without food.

34 . The method of any one of claims 1 to 33 , wherein the VMAT2 inhibitor is valbenazine or a pharmaceutically acceptable salt and/or isotopic variant thereof.

35 . The method of claim 34 , wherein the VMAT2 inhibitor is valbenazine or a pharmaceutically acceptable salt thereof.

36 . The method of claim 35 , wherein the VMAT2 inhibitor is a valbenazine tosylate salt.

37 . The method of claim 36 , wherein the VMAT2 inhibitor is a ditosylate salt of valbenazine.

38 . The method of claim 34 , wherein the VMAT2 inhibitor is an isotopic variant that is L-Valine, (2R,3R,11bR)-1,3,4,6,7,11b-hexahydro-9,10-di(methoxy-d3)-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-yl ester or a pharmaceutically acceptable salt thereof.

39 . The method of any one of claims 1 to 38 , wherein the VMAT2 inhibitor is administered in an amount equivalent to between about 20 mg and about 160 mg of valbenazine free base.

40 . The method of claim 39 , wherein the VMAT2 inhibitor is administered in an amount equivalent to about 20 mg of valbenazine free base.

41 . The method of claim 39 , wherein the VMAT2 inhibitor is administered in an amount equivalent to about 40 mg of valbenazine free base.

42 . The method of claim 39 , wherein the VMAT2 inhibitor is administered in an amount equivalent to about 60 mg of valbenazine free base.

43 . The method of claim 39 , wherein the VMAT2 inhibitor is administered in an amount equivalent to about 80 mg of valbenazine free base.

44 . The method of claim 39 , wherein the VMAT2 inhibitor is administered in an amount equivalent to about 120 mg of valbenazine free base.

45 . The method of any one of claims 1 to 38 , wherein the VMAT2 inhibitor is administered for a first period of time in a first amount and then the amount is increased to a second amount.

46 . The method of claim 43 , wherein the first period of time is a week.

47 . The method of claim 43 or 44 , wherein the first amount is equivalent to about 40 mg of valbenazine free base.

48 . The method of any one of claims 43 to 45 , wherein the second amount is equivalent to about 80 mg of valbenazine free base.

49 . The method of any one of claims 1 to 38 , wherein the VMAT2 inhibitor is administered in an amount sufficient to achieve a maximal blood plasma concentration (C max ) of (+)-α-DHTBZ of between about 15 ng to about 60 ng per mL plasma and a minimal blood plasma concentration (C min ) of (+)-α-DHTBZ of at least 15 ng per mL plasma over an 8 hour period.

50 . The method of any one of claims 1 to 38 , wherein the VMAT2 inhibitor is administered in an amount sufficient to achieve a maximal blood plasma concentration (C max ) of (+)-α-DHTBZ of between about 15 ng to about 60 ng per mL plasma and a minimal blood plasma concentration (C min ) of approximately between about at least 33% -50% of the C max over a 12 hour period.

51 . The method of any one of claims 1 to 38 , wherein the VMAT2 inhibitor is administered in an amount sufficient to achieve: (i) a therapeutic concentration range of about 15 ng to about 60 ng of (+)-α-DHTBZ per mL plasma; and (ii) a threshold concentration of at least 15 ng (+)-α-DHTBZ per mL plasma over a period of about 8 hours to about 24 hours.

52 . The method of any one of claims 1 to 38 , wherein the therapeutically effective amount of the VMAT2 inhibitor is 10-90% less than the amount that would be administered to a patient who is not a CYP2D6 poor metabolizer.

53 . The method of any one of claims 1 to 38 , wherein the therapeutically effective amount of the VMAT2 inhibitor is 20-80% less than the amount that would be administered to a patient who is not a CYP2D6 poor metabolizer.

54 . The method of any one of claims 1 to 38 , wherein the therapeutically effective amount of the VMAT2 inhibitor is 30-70% less than the amount that would be administered to a patient who is not a CYP2D6 poor metabolizer.

55 . The method of any one of claims 1 to 38 , wherein the therapeutically effective amount of the VMAT2 inhibitor is 40-60% less than the amount that would be administered to a patient who is not a CYP2D6 poor metabolizer.

56 . The method of any one of claims 1 to 38 , wherein the therapeutically effective amount of the VMAT2 inhibitor is about 50% less than the amount that would be administered to a patient who is not a CYP2D6 poor metabolizer.

57 . The method of any one of claims 1 to 33 , wherein the VMAT2 inhibitor is (+)-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.

58 . The method of claim 57 , wherein the VMAT2 inhibitor is (+)-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 thereof.

59 . The method of claim 57 , wherein the VMAT2 inhibitor is an isotopic variant that is (+)-α-3-isobutyl-9,10-di(methoxy-d 3 )-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol or a pharmaceutically acceptable salt thereof.

60 . A composition for treating a patient in need of 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, wherein the patient is a cytochrome P450 2D6 (CYP2D6) poor metabolizer, comprising:

a therapeutically effective amount of the VMAT2 inhibitor.

61 . The composition of claim 60 , wherein the patient is monitored for one or more exposure-related adverse reactions.

62 . The composition of claim 60 or 61 , characterized in that a composition comprising a reduced amount of the VMAT2 inhibitor is administered based on the patient's ability to tolerate one or more exposure-related adverse reactions following administration of the composition comprising the therapeutically effective amount of the VMAT2 inhibitor.

63 . A composition for treating a patient in need of 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, wherein the patient is a cytochrome P450 2D6 (CYP2D6) poor metabolizer, comprising:

the VMAT2 inhibitor,

characterized in that the composition comprising the VMAT2 inhibitor in an amount that would be less than that administered to a patient who is not a CYP2D6 poor metabolizer is administered to the patient subsequently determined to be a CYP2D6 poor metabolizer following administration of the composition comprising a therapeutically effective amount of the VMAT2 inhibitor.

64 . A composition for treating a patient in need of 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, wherein the patient is a cytochrome P450 2D6 (CYP2D6) poor metabolizer, comprising:

the VMAT2 inhibitor,

characterized in that the composition comprising the VMAT2 inhibitor in an amount that is the same as that administered to a patient who is not a CYP2D6 poor metabolizer is administered to the patient subsequently determined to be a CYP2D6 poor metabolizer following administration of the composition comprising a therapeutically effective amount of the VMAT2 inhibitor.

65 . The composition of claim 63 or 64 , wherein the patient is monitored for one or more exposure-related adverse reactions.

66 . The composition of any one of claims 63 to 65 , characterized in that the composition comprising a reduced amount of the VMAT2 inhibitor is administered based on the patient's ability to tolerate one or more exposure-related adverse reactions following administration of the composition comprising a therapeutically effective amount of the VMAT2 inhibitor as defined in claim 4 or the composition comprising a reduced amount of the VMAT2 inhibitor as defined in claim 5 .

67 . The composition of any one of claims 60 to 66 , wherein the patient or a medical care worker is informed that administration of the composition to a patient who is a CYP2D6 poor metabolizer may result in increased exposure of (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol.

68 . The composition of any one of claims 60 to 67 , wherein the patient or a medical care worker is informed that administration of the composition to a patient who is a CYP2D6 poor metabolizer may result in increased risk of one or more exposure-related adverse reactions.

69 . The composition of any one of claims 60 to 68 , wherein the patient or a medical care worker is informed that administration of the composition to a patient who is a CYP2D6 poor metabolizer may prolong the patient's QT interval.

70 . The composition of claims 60 to 69 , wherein the one or more exposure-related adverse reactions is chosen from somnolence, anticholinergic effects, balance disorders or falls, headache, akathisia, vomiting, nausea, arthralgia, QT prolongation, increase in blood glucose, increase in weight, respiratory infections, drooling, dyskinesia, extrapyramidal symptoms (non-akathisia), anxiety, insomnia, increase in prolactin, increase in alkaline phosphatase, and increase in bilirubin.

71 . The composition of claim 70 , wherein the one or more exposure-related adverse reactions is chosen from somnolence, anticholinergic effects, balance disorders or falls, headache, akathisia, vomiting, nausea, arthralgia, and QT prolongation.

72 . The composition of claim 71 , wherein the one or more exposure-related adverse reactions is chosen from somnolence and QT prolongation.

73 . The composition of any one of claims 60 to 72 , wherein the therapeutically effective amount is less than the amount that is administered to a patient who is not a CYP2D6 poor metabolizer.

74 . The composition of any one of claims 60 to 72 , wherein the therapeutically effective amount is the same amount as that administered to a patient who is not a CYP2D6 poor metabolizer.

75 . The composition of any one of claims 60 to 74 , wherein the patient has a CYP2D6 poor metabolizer genotype.

76 . The composition of claim 75 , wherein the CYP2D6 poor metabolizer genotype is chosen from the CYP2D6G1846A genotype or the CYP2D6C100T genotype.

77 . The composition of claim 76 , wherein the CYP2D6 poor metabolizer genotype is one of the CYP2D6G1846A (AA) genotype or the CYP2D6G1846A (AG) genotype.

78 . The composition of claim 77 , wherein the CYP2D6 poor metabolizer genotype is the CYP2D6G1846A (AA) genotype.

79 . The composition of claim 76 , wherein the CYP2D6 poor metabolizer genotype is one of the CYP2D6C100T (TT) genotype or the CYP2D6C100T (CT) genotype.

80 . The composition of claim 79 , wherein the CYP2D6 poor metabolizer genotype is the CYP2D6C100T (TT) genotype.

81 . The composition of any one of claims 60 to 80 , wherein the VMAT2 inhibitor is administered to the patient to treat a neurological or psychiatric disease or disorder.

82 . The composition of claim 81 , wherein the neurological or psychiatric disease or disorder is a hyperkinetic movement disorder, mood disorder, bipolar disorder, schizophrenia, schizoaffective disorder, mania in mood disorder, depression in mood disorder, treatment-refractory obsessive compulsive disorder, neurological dysfunction associated with Lesch-Nyhan syndrome, agitation associated with Alzheimer's disease, Fragile X syndrome or Fragile X-associated tremor-ataxia syndrome, autism spectrum disorder, Rett syndrome, or chorea-acanthocytosis.

83 . The composition of claim 82 , wherein the neurological or psychiatric disease or disorder is a hyperkinetic movement disorder.

84 . The composition of claim 83 , wherein the hyperkinetic movement disorder is tardive dyskinesia.

85 . The composition of claim 83 , wherein the hyperkinetic movement disorder is Tourette's syndrome.

86 . The composition of claim 83 , wherein the hyperkinetic movement disorder is Huntington's disease.

87 . The composition of claim 83 , wherein the hyperkinetic movement disorder is tics.

88 . The composition of claim 83 , wherein the hyperkinetic movement disorder is chorea associated with Huntington's disease.

89 . The composition of claim 83 , wherein the hyperkinetic movement disorder is ataxia, chorea, dystonia, Huntington's disease, myoclonus, restless leg syndrome, or tremors.

90 . The composition of any one of claims 60 to 89 , characterized in that the composition is administered orally.

91 . The composition of any one of claims 60 to 90 , characterized in that the composition is administered in the form of a tablet or capsule.

92 . The composition of any one of claims 60 to 91 , characterized in that the composition is administered with or without food.

93 . The composition of any one of claims 60 to 92 , wherein the VMAT2 inhibitor is valbenazine or a pharmaceutically acceptable salt and/or isotopic variant thereof.

94 . The composition of claim 93 , wherein the VMAT2 inhibitor is valbenazine or a pharmaceutically acceptable salt thereof.

95 . The composition of claim 94 , wherein the VMAT2 inhibitor is a valbenazine tosylate salt.

96 . The composition of claim 95 , wherein the VMAT2 inhibitor is a ditosylate salt of valbenazine.

97 . The composition of claim 93 , wherein the VMAT2 inhibitor is an isotopic variant that is L-Valine, (2R,3R,11bR)-1,3,4,6,7,11b-hexahydro-9,10-di(methoxy-d 3 )-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-yl ester or a pharmaceutically acceptable salt thereof.

98 . The composition of any one of claims 60 to 97 , wherein the VMAT2 inhibitor is administered in an amount equivalent to between about 20 mg and about 160 mg of valbenazine free base of the VMAT2 inhibitor.

99 . The composition of claim 98 , wherein the VMAT2 inhibitor is administered in an amount equivalent to about 20 mg of valbenazine free base of the VMAT2 inhibitor.

100 . The composition of claim 98 , wherein the VMAT2 inhibitor is administered in an amount equivalent to about 40 mg of valbenazine free base of the VMAT2 inhibitor.

101 . The composition of claim 98 , wherein the VMAT2 inhibitor is administered in an amount equivalent to about 60 mg of valbenazine free base of the VMAT2 inhibitor.

102 . The composition of claim 98 , wherein the VMAT2 inhibitor is administered in an amount equivalent to about 80 mg of valbenazine free base of the VMAT2 inhibitor.

103 . The composition of claim 98 , wherein the VMAT2 inhibitor is administered in an amount equivalent to about 120 mg of valbenazine free base of the VMAT2 inhibitor.

104 . The composition of any one of claims 60 to 97 , wherein the composition is administered for a first period of time in a first amount of the VMAT2 inhibitor and then the amount is increased to a second amount.

105 . The composition of claim 104 , wherein the first period of time is a week.

106 . The composition of claim 104 or 105 , wherein the first amount is equivalent to about 40 mg of valbenazine free base.

107 . The composition of any one of claims 104 to 106 , wherein the second amount is equivalent to about 80 mg of valbenazine free base.

108 . The composition of any one of claims 60 to 97 , wherein the VMAT2 inhibitor is administered in an amount sufficient to achieve a maximal blood plasma concentration (C max ) of (+)-α-DHTBZ of between about 15 ng to about 60 ng per mL plasma and a minimal blood plasma concentration (C min ) of (+)-α-DHTBZ of at least 15 ng per mL plasma over an 8 hour period.

109 . The composition of any one of claims 60 to 97 , wherein the VMAT2 inhibitor is administered in an amount sufficient to achieve a maximal blood plasma concentration (C max ) of (+)-α-DHTBZ of between about 15 ng to about 60 ng per mL plasma and a minimal blood plasma concentration (C min ) of approximately between about at least 33% -50% of the C max over a 12 hour period.

110 . The composition of any one of claims 60 to 97 , wherein the VMAT2 inhibitor is administered in an amount sufficient to achieve: (i) a therapeutic concentration range of about 15 ng to about 60 ng of (+)-α-DHTBZ per mL plasma; and (ii) a threshold concentration of at least 15 ng (+)-α-DHTBZ per mL plasma over a period of about 8 hours to about 24 hours.

111 . The composition of any one of claims 60 to 97 , characterized in that the amount of the VMAT2 inhibitor is 10-90% less than the amount that would be administered to a patient who is not a CYP2D6 poor metabolizer.

112 . The composition of any one of claims 60 to 97 , characterized in that the amount of the VMAT2 inhibitor is 20-80% less than the amount that would be administered to a patient who is not a CYP2D6 poor metabolizer.

113 . The composition of any one of claims 60 to 97 , characterized in that the amount of the VMAT2 inhibitor is 30-70% less than the amount that would be administered to a patient who is not a CYP2D6 poor metabolizer.

114 . The composition of any one of claims 60 to 97 , characterized in that the amount of the VMAT2 inhibitor is 40-60% less than the amount that would be administered to a patient who is not a CYP2D6 poor metabolizer.

115 . The composition of any one of claims 60 to 97 , characterized in that the amount of the VMAT2 inhibitor is about 50% less than the amount that would be administered to a patient who is not a CYP2D6 poor metabolizer.

116 . The composition of any one of claims 60 to 92 , wherein the VMAT2 inhibitor is (+)-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.

117 . The composition of claim 116 , wherein the VMAT2 inhibitor is (+)-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 thereof.

118 . The composition of claim 116 , wherein the VMAT2 inhibitor is an isotopic variant that is (+)-α-3-isobutyl-9,10-di(methoxy-d3)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol or a pharmaceutically acceptable salt thereof.