Methods for the Administration of Certain VMAT2 Inhibitors

Abstract

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 also being administered digoxin.

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 also being administered digoxin, comprising:
 administering to the patient a therapeutically effective amount of the VMAT2 inhibitor. 
 
     
     
         2 . The method of  claim 1 , further comprising monitoring the patient for signs and symptoms of digoxin toxicity and clinical response. 
     
     
         3 . The method of  claim 1  or  2 , further comprising reducing the amount of the digoxin administered to the patient based on the patient's ability to tolerate one or more digoxin 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 to begin treatment with digoxin, and 
 continuing administration of the therapeutically effective amount of the VMAT2 inhibitor to the patient. 
 
     
     
         5 . The method of  claim 4 , further comprising monitoring the patient signs and symptoms of digoxin toxicity and clinical response. 
     
     
         6 . The method of  claim 4  or  5 , further comprising reducing the amount of the digoxin administered to the patient based on the patient's ability to tolerate one or more digoxin exposure-related adverse reactions. 
     
     
         7 . 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 also being administered digoxin, comprising:
 administering a therapeutically effective amount of the VMAT2 inhibitor to the patient, 
 wherein the administration produces a mean digoxin C max  that is about 1.5 to 2.5 fold higher than the mean digoxin C max  for a patient who is administered digoxin alone and/or a mean digoxin AUC 0-∞  that is about 1 to about 2 fold higher than the mean digoxin AUC 0-∞  for a patient who is administered digoxin alone. 
 
     
     
         8 . The method of any one of  claims 1  to  7 , further comprising informing the patient or a medical care worker that co-administration of the VMAT2 inhibitor and digoxin may result in increased digoxin exposure. 
     
     
         9 . The method of any one of  claims 1  to  8 , further comprising informing the patient or a medical care worker that co-administration of the VMAT2 inhibitor and digoxin may result in increased risk of one or more digoxin exposure-related adverse reactions. 
     
     
         10 . The method of any one of  claims 1  to  9 , wherein monitoring for signs and symptoms of digoxin toxicity and clinical response comprises monitoring the serum concentration of the digoxin. 
     
     
         11 . The method of any one of  claims 1  to  9 , wherein monitoring for signs and symptoms of digoxin toxicity and clinical response comprises determining whether the patient experiences one or more exposure-related adverse reaction associated with serum digoxin concentration. 
     
     
         12 . The method of any one of  claims 1  to  9 , wherein monitoring for signs and symptoms of digoxin toxicity and clinical response comprises monitoring efficacy of the digoxin. 
     
     
         13 . The method of any one of  claims 1  to  3 , or  7  to  12 , further comprising obtaining a baseline serum digoxin concentration prior to administering to the patient the therapeutically effective amount of the VMAT2 inhibitor. 
     
     
         14 . The method of  claim 13 , further comprising obtaining a serum digoxin concentration after administering to the patient the therapeutically effective amount of the VMAT2 inhibitor. 
     
     
         15 . The method of  claim 14 , further comprising comparing the baseline serum digoxin concentration to the serum digoxin concentration after administering to the patient the therapeutically effective amount of the VMAT2 inhibitor. 
     
     
         16 . The method of any one of  claims 1  to  15 , wherein the dosage and/or frequency of administration of the digoxin is reduced. 
     
     
         17 . The method of  claim 16 , wherein the dosage of digoxin is decreased. 
     
     
         18 . The method of  claim 16  or  17 , wherein the frequency of administration of the digoxin is decreased. 
     
     
         19 . The method of any one of  claims 1  to  18 , wherein the VMAT2 inhibitor is administered to the patient to treat a neurological or psychiatric disease or disorder. 
     
     
         20 . The method of  claim 19 , 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. 
     
     
         21 . The method of  claim 20 , wherein the neurological or psychiatric disease or disorder is a hyperkinetic movement disorder. 
     
     
         22 . The method of  claim 21 , wherein the hyperkinetic movement disorder is tardive dyskinesia. 
     
     
         23 . The method of  claim 21 , wherein the hyperkinetic movement disorder is Tourette's syndrome. 
     
     
         24 . The method of  claim 21 , wherein the hyperkinetic movement disorder is Huntington's disease. 
     
     
         25 . The method of  claim 21 , wherein the hyperkinetic movement disorder is tics. 
     
     
         26 . The method of  claim 21 , wherein the hyperkinetic movement disorder is chorea associated with Huntington's disease. 
     
     
         27 . The method of  claim 21 , wherein the hyperkinetic movement disorder is ataxia, chorea, dystonia, Huntington's disease, myoclonus, restless leg syndrome, or tremors. 
     
     
         28 . The method of any one of  claims 1  to  27 , wherein the VMAT2 inhibitor is administered orally. 
     
     
         29 . The method of any one of  claims 1  to  28 , wherein the VMAT2 inhibitor is administered in the form of a tablet or capsule. 
     
     
         30 . The method of any one of  claims 1  to  29 , wherein the VMAT2 inhibitor is administered with or without food. 
     
     
         31 . The method of any one of  claims 1  to  30 , wherein the VMAT2 inhibitor is valbenazine or a pharmaceutically acceptable salt and/or isotopic variant thereof. 
     
     
         32 . The method of  claim 31 , wherein the VMAT2 inhibitor is valbenazine or a pharmaceutically acceptable salt thereof. 
     
     
         33 . The method of  claim 32 , wherein the VMAT2 inhibitor is a valbenazine tosylate salt. 
     
     
         34 . The method of  claim 33 , wherein the VMAT2 inhibitor is a ditosylate salt of valbenazine. 
     
     
         35 . The method of  claim 31 , 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. 
     
     
         36 . The method of any one of  claims 1  to  35 , wherein the VMAT2 inhibitor is administered in an amount equivalent to between about 20 mg and about 160 mg of valbenazine free base. 
     
     
         37 . The method of  claim 36 , wherein the VMAT2 inhibitor is administered in an amount equivalent to about 20 mg of valbenazine free base. 
     
     
         38 . The method of  claim 36 , wherein the VMAT2 inhibitor is administered in an amount equivalent to about 40 mg of valbenazine free base. 
     
     
         39 . The method of  claim 36 , wherein the VMAT2 inhibitor is administered in an amount equivalent to about 60 mg of valbenazine free base. 
     
     
         40 . The method of  claim 36 , wherein the VMAT2 inhibitor is administered in an amount equivalent to about 80 mg of valbenazine free base. 
     
     
         41 . The method of  claim 36 , wherein the VMAT2 inhibitor is administered in an amount equivalent to about 120 mg of valbenazine free base. 
     
     
         42 . The method of any one of  claims 1  to  35 , 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. 
     
     
         43 . The method of  claim 42 , wherein the first period of time is a week. 
     
     
         44 . The method of  claim 42  or  43 , wherein the first amount is equivalent to about 40 mg of valbenazine free base. 
     
     
         45 . The method of any one of  claims 42  to  44 , wherein the second amount is equivalent to about 80 mg of valbenazine free base. 
     
     
         46 . The method of any one of  claims 1  to  35 , 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. 
     
     
         47 . The method of any one of  claims 1  to  35 , 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 max ) of approximately between about at least 33%-50% of the C max  over a 12 hour period. 
     
     
         48 . The method of any one of  claims 1  to  35 , 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. 
     
     
         49 . The method of any one of  claims 1  to  35 , wherein the amount of digoxin being administered is 10-90% less than the amount that would be administered to a patient who is not also being administered a VMAT2 inhibitor. 
     
     
         50 . The method of any one of  claims 1  to  35 , wherein the amount of digoxin being administered is 20-80% less than the amount that would be administered to a patient who is not also being administered a VMAT2 inhibitor. 
     
     
         51 . The method of any one of  claims 1  to  35 , wherein the amount of digoxin being administered is 30-70% less than the amount that would be administered to a patient who is not also being administered a VMAT2 inhibitor. 
     
     
         52 . The method of any one of  claims 1  to  35 , wherein the amount of digoxin being administered is 40-60% less than the amount that would be administered to a patient who is not also being administered a VMAT2 inhibitor. 
     
     
         53 . The method of any one of  claims 1  to  35 , wherein the amount of digoxin being administered is 50% less than the amount that would be administered to a patient who is not also being administered a VMAT2 inhibitor 
     
     
         54 . The method of any one of  claims 1  to  30 , 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. 
     
     
         55 . The method of  claim 54 , 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 dihydrotetrabenazine or a pharmaceutically acceptable salt thereof. 
     
     
         56 . The method of  claim 54 , 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. 
     
     
         57 . 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 and being administered digoxin, comprising:
 a therapeutically effective amount of the VMAT2 inhibitor. 
 
     
     
         58 . The composition of  claim 57 , wherein the patient is monitored for signs and symptoms of digoxin toxicity and clinical response. 
     
     
         59 . The composition of  claim 57  or  58 , characterized in that a composition comprising a reduced amount of the digoxin is administered to the patient based on the patient's ability to tolerate one or more digoxin exposure-related adverse reactions following administration of the composition comprising the therapeutically effective amount of the VMAT2 inhibitor. 
     
     
         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, comprising the VMAT2 inhibitor,
 characterized in that the composition comprising a therapeutically effective amount of the VMAT2 inhibitor is administered to the patient subsequently determined to begin treatment with digoxin following administration of the composition comprising the 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 any one of  claim 60  or  61 , 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 . 
     
     
         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, and being treated with digoxin, comprising:
 a therapeutically effective amount of the VMAT2 inhibitor, 
 wherein administration of the composition produces a mean digoxin C max  that is about 1.5 to 2.5 fold higher than the mean digoxin C max  for a patient who is administered digoxin alone and/or a mean digoxin AUC 0-∞  that is about 1 to about 2 fold higher than the mean digoxin AUC 0-∞  for a patient who is administered digoxin alone. 
 
     
     
         64 . The composition of any one of  claims 57  to  63 , wherein the patient or a medical care worker is informed that co-administration of the composition and digoxin may result in increased digoxin exposure. 
     
     
         65 . The composition of any one of  claims 57  to  64 , wherein the patient or a medical care worker is informed that co-administration of the composition and digoxin may result in increased risk of one or more digoxin exposure-related adverse reactions. 
     
     
         66 . The composition of any one of  claims 57  to  65 , wherein the serum concentration of digoxin is monitored. 
     
     
         67 . The composition of any one of  claims 57  to  66 , wherein the dosage and/or frequency of administration of the digoxin is reduced. 
     
     
         68 . The composition of  claim 67 , wherein the dosage of digoxin is decreased. 
     
     
         69 . The composition of  claim 67  or  68 , wherein the frequency of administration of the digoxin is decreased. 
     
     
         70 . The composition of any one of  claims 57  to  69 , wherein the composition is for treating a neurological or psychiatric disease or disorder. 
     
     
         71 . The composition of  claim 70 , 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. 
     
     
         72 . The composition of  claim 71 , wherein the neurological or psychiatric disease or disorder is a hyperkinetic movement disorder. 
     
     
         73 . The composition of  claim 72 , wherein the hyperkinetic movement disorder is tardive dyskinesia. 
     
     
         74 . The composition of  claim 72 , wherein the hyperkinetic movement disorder is Tourette's syndrome. 
     
     
         75 . The composition of  claim 72 , wherein the hyperkinetic movement disorder is Huntington's disease. 
     
     
         76 . The composition of  claim 72 , wherein the hyperkinetic movement disorder is tics. 
     
     
         77 . The composition of  claim 72 , wherein the hyperkinetic movement disorder is chorea associated with Huntington's disease. 
     
     
         78 . The composition of  claim 72 , wherein the hyperkinetic movement disorder is ataxia, chorea, dystonia, Huntington's disease, myoclonus, restless leg syndrome, or tremors. 
     
     
         79 . The composition of any one of  claims 57  to  78 , characterized in that the composition is administered orally. 
     
     
         80 . The composition of any one of  claims 57  to  79 , characterized in that the composition is administered in the form of a tablet or capsule. 
     
     
         81 . The composition of any one of  claims 57  to  80 , characterized in that the composition is administered with or without food. 
     
     
         82 . The composition of any one of  claims 57  to  81 , wherein the VMAT2 inhibitor is valbenazine or a pharmaceutically acceptable salt and/or isotopic variant thereof. 
     
     
         83 . The composition of  claim 82 , wherein the VMAT2 inhibitor is valbenazine or a pharmaceutically acceptable salt thereof. 
     
     
         84 . The composition of  claim 83 , wherein the VMAT2 inhibitor is a valbenazine tosylate salt. 
     
     
         85 . The composition of  claim 84 , wherein the VMAT2 inhibitor is a ditosylate salt of valbenazine. 
     
     
         86 . The composition of  claim 82 , 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. 
     
     
         87 . The composition of any one of  claims 57  to  86 , characterized in that the composition is administered in an amount equivalent to between about 20 mg and about 160 mg of valbenazine free base of the VMAT2 inhibitor. 
     
     
         88 . The composition of  claim 87 , wherein characterized in that the composition is administered in an amount equivalent to about 20 mg of valbenazine free base of the VMAT2 inhibitor. 
     
     
         89 . The composition of  claim 87 , characterized in that the composition is administered in an amount equivalent to about 40 mg of valbenazine free base of the VMAT2 inhibitor. 
     
     
         90 . The composition of  claim 87 , characterized in that the composition is administered in an amount equivalent to about 60 mg of valbenazine free base of the VMAT2 inhibitor. 
     
     
         91 . The composition of  claim 87 , characterized in that the composition is administered in an amount equivalent to about 80 mg of valbenazine free base of the VMAT2 inhibitor. 
     
     
         92 . The composition of  claim 87 , characterized in that the composition is administered in an amount equivalent to about 120 mg of valbenazine free base of the VMAT2 inhibitor. 
     
     
         93 . The composition of any one of  claims 57  to  86 , characterized in that 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 of the VMAT2 inhibitor. 
     
     
         94 . The composition of  claim 93 , wherein the first period of time is a week. 
     
     
         95 . The composition of  claim 93  or  94 , wherein the first amount is equivalent to about 40 mg of valbenazine free base. 
     
     
         96 . The composition of any one of  claims 93  to  95 , wherein the second amount is equivalent to about 80 mg of valbenazine free base. 
     
     
         97 . The composition of any one of  claims 57  to  86 , characterized in that the composition 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. 
     
     
         98 . The composition of any one of  claims 57  to  86 , characterized in that the composition 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. 
     
     
         99 . The composition of any one of  claims 57  to  86 , characterized in that the composition 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. 
     
     
         100 . The composition of any one of  claims 57  to  86 , characterized in that the amount of digoxin being administered is 10-90% less than the amount that would be administered to a patient who is not also being administered a VMAT2 inhibitor. 
     
     
         101 . The composition of any one of  claims 57  to  86 , characterized in that the amount of digoxin being administered is 20-80% less than the amount that would be administered to a patient who is not also being administered a VMAT2 inhibitor. 
     
     
         102 . The composition of any one of  claims 57  to  86 , characterized in that the amount of digoxin being administered is 30-70% less than the amount that would be administered to a patient who is not also being administered a VMAT2 inhibitor. 
     
     
         103 . The composition of any one of  claims 57  to  86 , characterized in that the amount of digoxin being administered is 40-60% less than the amount that would be administered to a patient who is not also being administered a VMAT2 inhibitor. 
     
     
         104 . The composition of any one of  claims 57  to  86 , characterized in that the amount of digoxin being administered is 50% less than the amount that would be administered to a patient who is not also being administered a VMAT2 inhibitor 
     
     
         105 . The composition of any one of  claims 57  to  81 , characterized in that 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. 
     
     
         106 . The composition of  claim 105 , 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 dihydrotetrabenazine or a pharmaceutically acceptable salt thereof. 
     
     
         107 . The composition of  claim 105 , 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.