Methods for the treatment of abnormal involuntary movement disorders

Abstract

Disclosed herein are new dosage regimens for deuterium-substituted benzoquinoline compounds, and methods for the treatment of abnormal muscular activity, movement disorders, and related conditions.

1 . A method of treating abnormal involuntary movement in a subject, comprising:
 a) administering to the subject an initial daily amount of deutetrabenazine of at least about 6 mg/day;   b) determining the degree of control of abnormal involuntary movement achieved with the initial daily amount and the tolerability of the initial daily amount after about one week;   c) increasing the daily amount of the deutetrabenazine by at least about 6 mg/day to a first subsequent daily amount if the abnormal involuntary movement is not reduced and the initial daily amount is tolerable;   d) optionally, repeating steps b) and c) after about one week until abnormal involuntary movement is reduced and the first subsequent daily amount of the deutetrabenazine is tolerable; and   e) decreasing the daily amount by at least about 6 mg/day to a second subsequent daily amount if said first subsequent daily amount is not tolerated.   
     
     
         2 - 6 . (canceled) 
     
     
         7 . The method as recited in  claim 1 , wherein the subject has Huntington's disease. 
     
     
         8 - 9 . (canceled) 
     
     
         10 . The method as recited in  claim 7 , wherein the subject has chorea associated with Huntington's disease. 
     
     
         11 - 14 . (canceled) 
     
     
         15 . The method as recited in  claim 1 , wherein initial daily amount of deutetrabenazine is about 30% to about 70% of tetrabenazine that provides adequate control of the abnormal involuntary movement. 
     
     
         16 . The method as recited in  claim 1 , wherein the daily amount of deutetrabenazine is administered in one dose or two doses. 
     
     
         17 . The method as recited in  claim 1 , wherein the initial daily amount of deutetrabenazine is about 6 mg to about 48 mg. 
     
     
         18 . (canceled) 
     
     
         19 . The method as recited in  claim 16 , wherein:
 the first dose is about 6 mg and the second dose is about 6 mg;   the first dose is about 9 mg and the second dose is about 9 mg;   the first dose is about 12 mg and the second dose is about 12 mg;   the first dose is about 15 mg and the second dose is about 15 mg;   the first dose is about 18 mg and the second dose is about 18 mg;   the first dose is about 21 mg and the second dose is about 21 mg; and   the first dose is about 24 mg and the second dose is about 24 mg.   
     
     
         20 . The method as recited in  claim 1 , wherein the daily amount of deutetrabenazine administered is less than or equal to about 48 mg, or less than or equal to about 36 mg for a subject concurrently receiving a strong CYP2D6 inhibitor. 
     
     
         21 . The method as recited in  claim 20 , wherein the strong CYP2D6 inhibitor is fluoxetine, aroxetine, bupropion, quinidine, or cinacalcet. 
     
     
         22 . The method as recited in  claim 10 , wherein chorea is reduced by at least 0.5 points as measured by the Total Maximal Chorea (TMC) score of the Unified Huntington's Disease Rating Scale (UHDRS). 
     
     
         23 - 26 . (canceled) 
     
     
         27 . The method as recited in  claim 10 , wherein chorea is reduced by at least 10%. 
     
     
         28 - 30 . (canceled) 
     
     
         31 . The method as recited in  claim 1 , wherein motor function is improved by a reduction of at least 1 point as measured by the Total Motor Score (TMS) of the Unified Huntington's Disease Rating Scale (UHDRS). 
     
     
         32 - 43 . (canceled) 
     
     
         44 . A method of transitioning a subject from tetrabenazine to deutetrabenazine, said method comprising:
 a) discontinuing a daily amount of tetrabenazine;   b) administering an initial daily amount of deutetrabenazine the next day to the subject, wherein said initial daily amount is about 30% to about 70% of the daily amount of tetrabenazine and at least about 6 mg/day;   c) determining the degree of control of abnormal involuntary movement achieved with the initial daily amount of deutetrabenazine and the tolerability of the initial daily amount after about one week;   d) increasing the initial daily amount of deutetrabenzaine by at least about 6 mg/day to a first subsequent daily amount if the degree of control of abnormal involuntary movement is not improved and the initial amount is tolerated;   e) optionally, repeating steps c) and d) after about one week until abnormal involuntary movement is reduced and the first subsequent daily amount is tolerated; and   f) optionally, decreasing the first subsequent daily amount of deutetrabenzaine by about 6 mg/day to a second subsequent daily amount if said first subsequent amount is not tolerated.   
     
     
         45 - 84 . (canceled) 
     
     
         85 . A method of treating a movement disorder in a subject, said method comprising administering a daily amount of deutetrabenazine in the range of about 6 mg to about 78 mg, wherein:
 (i) chorea is reduced by at least 10% and said method also provides at least one of the following:   motor function is improved by at least 10%;   the subject's physical functioning is improved;   swallowing is improved;   balance is not worsened;   treatment causes no significant increase in insomnia, depression, anxiety, agitation, suicidal ideation, akathisia, irritability, fatigue, parkinsonism or dysphagia;   the maximal increases in QTcF is less than 5 ms;   or combinations thereof; or   (ii) motor function is improved by at least 10%, and said method also provides at least one of the following:   chorea is reduced by at least 10%;   the subject's physical functioning is improved;   swallowing is improved;   balance is not worsened;   treatment causes no significant increase in insomnia, depression, anxiety, agitation, suicidal ideation, akathisia, irritability, fatigue, parkinsonism or dysphagia;   the maximal increases in QTcF is less than 5 ms;   or combinations thereof.   
     
     
         86 . The method as recited in  claim 85 , wherein the movement disorder is Huntington's disease. 
     
     
         87 . The method as recited in  claim 85 , wherein the movement disorder is chorea associated with Huntington's disease. 
     
     
         88 . (canceled) 
     
     
         89 . The method as recited in  claim 85 , wherein the daily amount of deutetrabenazine is administered in one dose or two doses. 
     
     
         90 . The method as recited in  claim 89 , wherein the initial daily amount of deutetrabenazine is about 6 mg to about 78 mg. 
     
     
         91 . (canceled) 
     
     
         92 . The method as recited in  claim 89 , wherein:
 the first dose about 6 mg and the second dose is about 6 mg;   the first dose about 9 mg and the second dose is about 9 mg;   the first dose about 12 mg and the second dose is about 12 mg;   the first dose about 15 mg and the second dose is about 15 mg;   the first dose about 18 mg and the second dose is about 18 mg;   the first dose about 21 mg and the second dose is about 21 mg;   the first dose about 24 mg and the second dose is about 24 mg;   the first dose about 27 mg and the second dose is about 27 mg;   the first dose about 30 mg and the second dose is about 30 mg;   the first dose about 33 mg and the second dose is about 33 mg;   the first dose about 36 mg and the second dose is about 36 mg; and   the first dose about 39 mg and the second dose is about 39 mg.   
     
     
         93 . The method as recited in  claim 85 , wherein the chorea control is improved by a reduction of at least 0.5 points on the Total Maximal Chorea (TMC) score. 
     
     
         94 - 97 . (canceled) 
     
     
         98 . The method as recited in  claim 85 , wherein chorea is reduced by at least 15%. 
     
     
         99 - 108 . (canceled) 
     
     
         109 . A method of treating abnormal involuntary movement in a subject, said method comprising administering a daily amount of deutetrabenazine to the subject, wherein:
 a) the abnormal involuntary movement is reduced in said subject; and   b) one or more symptom of depression, insomnia, somnolence, fatigue, dizziness, restlessness, agitation, akathisia, parkinsonism, nausea, anxiety, impaired swallowing, body weight gain, irritability, or compulsive behavior is improved in said subject.   
     
     
         110 . The method as recited in  claim 109 , further comprising:
 (i) determining after about one week of treatment the degree of control of abnormal involuntary movement achieved with the initial daily amount of deutetrabenazine and the tolerability of the initial daily amount; and   (ii) increasing the daily amount of the deutetrabenazine by at least about 6 mg/day to a first subsequent daily amount if abnormal involuntary movement is not reduced and the initial daily amount is tolerated;   (iii) optionally, repeating steps i) and ii) after one week until abnormal involuntary movement is reduced and the first subsequent daily amount is tolerated; and   (iv) decreasing the daily amount by at least about 6 mg/day to a second subsequent daily amount if any amount is not tolerated.   
     
     
         111 - 113 . (canceled) 
     
     
         114 . The method as recited in  claim 109 , wherein the abnormal involuntary movement is chorea associated with Huntington's disease. 
     
     
         115 . (canceled) 
     
     
         116 . The method as recited in  claim 109 , wherein the daily amount of deutetrabenazine is administered in one dose or two doses. 
     
     
         117 . The method as recited in  claim 109 , wherein the initial daily amount of deutetrabenazine is about 6 mg to about 48 mg. 
     
     
         118 . (canceled) 
     
     
         119 . The method as recited in  claim 116 , wherein:
 the first dose about 6 mg and the second dose is about 6 mg;   the first dose about 9 mg and the second dose is about 9 mg;   the first dose about 12 mg and the second dose is about 12 mg;   the first dose about 15 mg and the second dose is about 15 mg;   the first dose about 18 mg and the second dose is about 18 mg;   the first dose about 21 mg and the second dose is about 21 mg; and   the first dose about 24 mg and the second dose is about 24 mg.   
     
     
         120 . The method as recited in  claim 119 , wherein the daily amount of deutetrabenazine administered is less than or equal to about 48 mg, or less than or equal to about 36 mg for a subject concurrently receiving a strong CYP2D6 inhibitor. 
     
     
         121 . The method as recited in  claim 120 , wherein the strong CYP2D6 inhibitor is fluoxetine, aroxetine, bupropion, quinidine, is cinacalcet. 
     
     
         122 . The method as recited in  claim 114 , wherein chorea control is improved by a reduction of at least 0.5 points as measured by the Total Maximal Chorea (TMC) score of the Unified Huntington's Disease Rating Scale (UHDRS). 
     
     
         123 - 126 . (canceled) 
     
     
         127 . The method as recited in  claim 114 , wherein chorea is reduced by at least 10%. 
     
     
         128 - 130 . (canceled) 
     
     
         131 . The method as recited in  claim 114 , wherein motor function is improved by a reduction of at least 1 point as measured by the Total Motor Score (TMS) of the Unified Huntington's Disease Rating Scale (UHDRS). 
     
     
         132 - 143 . (canceled) 
     
     
         144 . A method of reducing chorea and improving motor function in a subject with Huntington's disease, said method comprising administering a daily amount of deutetrabenazine. 
     
     
         145 . A method of improving motor function in a subject with Huntington's disease, tardive dyskinesia, or Tourette syndrome, said method comprising administering a daily amount of deutetrabenazine. 
     
     
         146 . A method of reducing motor or phonic tics in a subject with Tourette syndrome, comprising the administration of about a daily amount of deutetrabenazine. 
     
     
         147 - 160 . (canceled) 
     
     
         161 . A method of reducing motor and phonic tics in a subject with Tourette syndrome, comprising the administration of about a daily amount of deutetrabenazine. 
     
     
         162 - 175 . (canceled) 
     
     
         176 . A method of reducing tic severity in a subject with Tourette syndrome, comprising the administration of about a daily amount of deutetrabenazine, wherein the subject's reduction of tic severity is measured by the subject's Tourette Syndrome Patient Global Impression of Severity (TS-PGIS). 
     
     
         177 - 186 . (canceled) 
     
     
         187 . A method of maintaining control of abnormal involuntary movements in a human subject with a movement disorder, comprising administering to the subject a therapeutically effective amount of deutetrabenazine for a period of time sufficient to do one or more of the following:
 reduce chorea by at least 10%;   improve motor function by at least 10%;   improve physical functioning;   improve swallowing;   improve balance;   reduce abnormal involuntary movements in subjects with tardive dyskinesia;   reduce motor tics; or   reduce vocal/phonic tics.   
     
     
         188 . The method as recited in  claim 187  wherein the disorder is Huntington's disease. 
     
     
         189 . (canceled) 
     
     
         190 . The method as recited in  claim 187  wherein the sufficient period of time is at least four weeks. 
     
     
         191 - 192 . (canceled) 
     
     
         193 . The method as recited in  claim 187  wherein the reduction or improvement in the relevant measure or measures is by at least 10% over baseline. 
     
     
         194 - 196 . (canceled) 
     
     
         197 . The method as recited in  claim 187  wherein the disorder is Huntington's disease. 
     
     
         198 . The method as recited in  claim 187  wherein the abnormal involuntary movement is chorea associated with Huntington's disease. 
     
     
         199 - 201 . (canceled) 
     
     
         202 . The method of  claim 93 , wherein the improvement is measured from a pre-treatment, baseline to maintenance therapy.