METHODS FOR THE ADMINISTRATION OF CERTAIN VMAT2 INHIBITORS
Provided is a method of treating a neurological or psychiatric disease or disorder in a patient in need thereof, comprising: administering a vesicular monoamine transporter 2 (VMAT2) inhibitor to the patient in need thereof wherein the patient is a CYP2D6 poor metabolizer.
1 . A method of treating a neurological or psychiatric disease or disorder in a patient in need thereof, comprising:
administering a maximum total daily dose of between about 6 mg/day and about 30 mg/day of a vesicular monoamine transporter 2 (VMAT2) inhibitor to the patient in need thereof, wherein the patient a CYP2D6 poor metabolizer,
wherein the VMAT2 inhibitor is (RR,SS)-1, 3, 4, 6, 7, 11b-hexahydro-9,10-di(methoxy-d3)-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-one (deutetrabenazine),
wherein the administering occurs outside of a clinical trial setting.
2 . A method of treating a neurological or psychiatric disease or disorder in a patient in need thereof, comprising:
administering to the patient a maximum total daily dose of deutetrabenazine, that is between about 6 mg/day and about 30 mg/day if, and because, the patient is a CYP2D6 poor metabolizer,
wherein the administering occurs outside of a clinical trial setting.
3 . A method of treating a neurological or psychiatric disease or disorder in a patient in need thereof, wherein the patient is a CYP2D6 poor metabolizer comprising:
administering to the patient a maximum total daily dose of between 6 mg/day and about 30 mg/day of a vesicular monoamine transporter 2 (VMAT2) inhibitor,
wherein the VMAT2 inhibitor is deutetrabenazine,
monitoring the concentration of [−]-α-DHTBZ and/or [−]-β-DHTBZ in the patient's blood; and
reducing the amount of the VMAT2 inhibitor being administered when the [−]-α-DHTBZ and/or [−]-β-DHTBZ exposure in the patient's blood is increased as compared with the [−]-α-DHTBZ and/or [−]-β-DHTBZ level in a patient who is administered the VMAT2 inhibitor alone,
wherein the administering occurs outside of a clinical trial setting.
4 . The method of claim 3 , wherein the [−]-α-DHTBZ and [−]-β-DHTBZ exposures are measured as the area under the plasma concentration versus time curve from 0 hours extrapolated to infinity or measured as the maximum observed blood plasma concentration (C max ) at the time of maximum plasma concentration (t max ).
5 . The method of claim 3 or 4 , wherein the increased [−]-α-DHTBZ and/or [−]-β-DHTBZ exposure increases the risk of one or more exposure-related adverse reactions.
6 . A method of treating a neurological or psychiatric disease or disorder in a patient in need thereof, comprising:
administering about 48 mg/day of a vesicular monoamine transporter 2 (VMAT2) inhibitor to the patient in need thereof, wherein the VMAT2 inhibitor is deutetrabenazine,
subsequently determining that the patient is a CYP2D6 poor metabolizer and
administering a maximum total daily dose of between about 6 mg/day and about 30 mg/day of a vesicular monoamine transporter 2 (VMAT2) inhibitor to the patient in need thereof,
wherein the administering occurs outside of a clinical trial setting.
7 . A method of decreasing a risk of QT prolongation in a patient being treated for a neurological or psychiatric disease or disorder with deutetrabenazine, comprising:
administering to the patient a maximum total daily dose of deutetrabenazine that is between about 6 mg/day and about 30 mg/day if, and because, the patient is a CYP2D6 poor metabolizer,
wherein the administering occurs outside of a clinical trial setting.
8 . A method of reducing off-target activity and increasing on-target activity in a patient being treated for a neurological or psychiatric disease or disorder with deutetrabenazine, comprising:
administering to the patient a maximum total daily dose of deutetrabenazine that is between about 6 mg/day and about 30 mg/day if, and because, the patient is a CYP2D6 poor metabolizer,
wherein the administering occurs outside of a clinical trial setting.
9 . The method of claim 8 , wherein the off-target effects are caused by (−)-α-3-isobutyl-9,10-di(methoxy-d3)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol ([−]-α-DHTBZ) and (−)-β-3-isobutyl-9,10-di(methoxy-d3)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol ([−]-β-DHTBZ).
10 . The method of claim 8 , wherein the [−]-α-DHTBZ and [−]-β-DHTBZ activate an off-target receptor chosen from serotonin 5-HT7 receptor and dopamine D2 receptors.
11 . The method of claim 8 , wherein the on-target effects are caused by (+)-β-3-isobutyl-9,10-di(methoxy-d3)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol ([+]-β-DHTBZ).
12 . The method of any one of the preceding claims , wherein the patient has a CYP2D6 poor metabolizer genotype.
13 . The method of claim 12 , wherein the CYP2D6 poor metabolizer genotype is chosen from the CYP2D6G1846A genotype or the CYP2D6C100T genotype.
14 . The method of claim 13 , wherein the CYP2D6 poor metabolizer genotype is the CYP2D6G1846A (AA) genotype or the CYP2D6G1846A (AG) genotype.
15 . The method of claim 14 , wherein the CYP2D6 poor metabolizer genotype is the CYP2D6G1846A (AA) genotype.
16 . The method of claim 13 , wherein the CYP2D6 poor metabolizer genotype is the CYP2D6C100T (TT) genotype or the CYP2D6C100T (CT) genotype.
17 . The method of claim 16 , wherein the CYP2D6 poor metabolizer genotype is the CYP2D6C100T (TT) genotype.
18 . The method of any one of the preceding claims , 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.
19 . The method of claim 18 , wherein the neurological or psychiatric disease or disorder is a hyperkinetic movement disorder.
20 . The method of claim 18 , wherein the hyperkinetic movement disorder is tardive dyskinesia.
21 . The method of claim 18 , wherein the hyperkinetic movement disorder is Tourette's syndrome.
22 . The method of claim 18 , wherein the hyperkinetic movement disorder is Huntington's disease.
23 . The method of claim 18 , wherein the hyperkinetic movement disorder is tics.
24 . The method of claim 18 , wherein the hyperkinetic movement disorder is chorea associated with Huntington's disease.
25 . The method of claim 18 , wherein the hyperkinetic movement disorder is ataxia, chorea, dystonia, Huntington's disease, myoclonus, restless leg syndrome, or tremors.
26 . The method of any one of the preceding claims , wherein the maximum daily dose is about 24 mg.
27 . The method of claim 26 , wherein the maximum daily dose is administered in a maximum single dose of about 12 mg.
28 . The method of any one of claims 1 to 25 , wherein the maximum daily dose is about 20 mg.
29 . The method of claim 28 , wherein the maximum daily dose is administered in a maximum single dose of about 10 mg.
30 . The method of any one of claims 1 to 25 , wherein the maximum daily dose is about 18 mg.
31 . The method of claim 30 , wherein the maximum daily dose is administered in a maximum single dose of about 9 mg.
32 . The method of any one of claims 1 to 25 , wherein the maximum daily dose is about 12 mg.
33 . The method of claim 32 , wherein the maximum daily dose is administered in a maximum single dose of about 6 mg.
34 . The method of any one of the preceding claims , further comprising monitoring the patient for one or more exposure-related adverse reactions.
35 . The method of any one of the preceding claims , further comprising reducing the amount of the VMAT2 inhibitor based on the patient's ability to tolerate one or more exposure-related adverse reactions.
36 . The method of any one of the preceding claims , 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.
37 . The method of any one of the preceding claims , 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.
38 . The method of any one of claims 34 to 37 , wherein the one or more exposure-related adverse reactions is chosen from somnolence and sedation.
39 . The method of any one of claims 34 to 37 , wherein the one or more exposure-related adverse reactions is chosen from QTc prolongation, neuroleptic malignant syndrome (NMS), akathisia, agitation, restlessness, parkinsonism, sedation, somnolence, hyperprolactinemia, and binding to melanin-containing tissues.
40 . The method of any one of claims 34 to 37 , wherein the neurological or psychiatric disease or disorder is chorea associated with Huntington's disease is one or more exposure-related adverse reactions is chosen from diarrhea, dry mouth, fatigue, sedation/somnolence, depression and suicidality, parkinsonism, akathisia, restlessness, and cognitive decline, urinary tract infection, insomnia, anxiety, constipation, and contusion.
41 . The method of any one of claims 34 to 37 , wherein the neurological or psychiatric disease or disorder is tardive dyskinesia is one or more exposure-related adverse reactions is chosen from nasopharyngitis, insomnia, depression/dysthymic disorder, and Akathisia/Agitation/Restlessness.
42 . The method of any one of the preceding claims , wherein the VMAT2 inhibitor is administered orally.
43 . The method of any one of the preceding claims , wherein the VMAT2 inhibitor is administered in the form of a tablet or capsule.