METHODS FOR THE COMBINED ADMINISTRATION OF DEUTETRABENAZINE AND A CYP2D6 INHIBITOR

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, the patient also being administered a strong cytochrome P450 2D6 (CYP2D6) inhibitor,

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).

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 also being treated with a strong cytochrome P450 2D6 (CYP2D6) inhibitor.

3 . A method of treating a neurological or psychiatric disease or disorder in a patient in need thereof, wherein the patient is also being administered a strong cytochrome P450 2D6 (CYP2D6) inhibitor 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.

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, wherein the patient is being treated with a strong cytochrome P450 2D6 (CYP2D6) inhibitor, comprising:

discontinuing treatment of the strong CYP2D6 inhibitor and then

administering a VMAT2 inhibitor to the patient, wherein the VMAT2 inhibitor is deutetrabenazine,

thereby avoiding the use of the VMAT2 inhibitor in combination with the strong CYP2D6 inhibitor.

7 . 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 to begin treatment with a strong cytochrome P450 2D6 (CYP2D6) inhibitor, 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.

8 . 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 being treated with a strong cytochrome P450 2D6 (CYP2D6) inhibitor.

9 . 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 being treated with a strong cytochrome P450 2D6 (CYP2D6) inhibitor.

10 . The method of claim 9 , 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).

11 . The method of claim 9 , wherein the [−]-α-DHTBZ and [−]-β-DHTBZ activate an off-target receptor chosen from serotonin 5-HT7 receptor and dopamine D2 receptors.

12 . The method of claim 9 , 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).

13 . The method of any one of the preceding claims , wherein the treatment occurs outside of a clinical trial setting.

14 . The method of any one of the preceding claims , wherein the strong CYP2D6 inhibitor is chosen from bupropion, cinacalcet, cisapride, dacomitinib, duloxetine, fluoxetine, glycerol phenylbutyrate, halofantrine, metoclopramide, methotrimeprazine, midostaurin, orphenadrine, paroxetine, propafenone, quinidine, sertraline, terbinafine, thioridazine, and tipranavir.

15 . The method of claim 14 , wherein the strong CYP2D6 inhibitor is chosen from bupropion, fluoxetine, paroxetine, and quinidine.

16 . 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.

17 . The method of claim 16 , wherein the neurological or psychiatric disease or disorder is a hyperkinetic movement disorder.

18 . The method of claim 16 , wherein the hyperkinetic movement disorder is tardive dyskinesia.

19 . The method of claim 16 , wherein the hyperkinetic movement disorder is Tourette's syndrome.

20 . The method of claim 16 , wherein the hyperkinetic movement disorder is Huntington's disease.

21 . The method of claim 16 , wherein the hyperkinetic movement disorder is tics.

22 . The method of claim 16 , wherein the hyperkinetic movement disorder is chorea associated with Huntington's disease.

23 . The method of claim 16 , wherein the hyperkinetic movement disorder is ataxia, chorea, dystonia, Huntington's disease, myoclonus, restless leg syndrome, or tremors.

24 . The method of any one of claims 1 to 23 , wherein the maximum total daily dose is about 24 mg.

25 . The method of claim 24 , wherein the maximum total daily dose is administered with a maximum single dose of about 12 mg.

26 . The method of any one of claims 1 to 23 , wherein the maximum total daily dose is about 20 mg.

27 . The method of claim 26 , wherein the maximum total daily dose is administered with a maximum single dose of about 10 mg.

28 . The method of any one of claims 1 to 23 , wherein the maximum total daily dose is about 18 mg.

29 . The method of claim 28 , wherein the maximum total daily dose is administered with a maximum single dose of about 9 mg.

30 . The method of any one of claims 1 to 23 , wherein the maximum total daily dose is about 12 mg.

31 . The method of claim 30 , wherein the maximum total daily dose is administered with a maximum single dose of about 6 mg.

32 . The method of any one of the preceding claims , further comprising monitoring the patient for one or more exposure-related adverse reactions.

33 . 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.

34 . 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 also being administered a strong CYP2D6 inhibitor may result in increased risk of one or more exposure-related adverse reactions.

35 . The method of any one of the preceding claims , further comprising informing the patient or a medical care worker that co-administration of the VMAT2 inhibitor and a strong CYP2D6 inhibitor may prolong the patient's QT interval.

36 . The method of any one of claims 32 to 35 , wherein the one or more exposure-related adverse reactions is chosen from somnolence and sedation.

37 . The method of any one of claims 32 to 35 , 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.

38 . The method of any one of claims 32 to 35 , 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.

39 . The method of any one of claims 32 to 35 , 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.

40 . The method of any one of the preceding claims , wherein the VMAT2 inhibitor is administered orally.

41 . The method of any one of the preceding claims , wherein the VMAT2 inhibitor is administered in the form of a tablet or capsule.