Methods for enhancing the bioavailability and exposure of a voltage-gated potassium channel opener

Abstract

In certain embodiments, the present disclosure is directed to methods and uses for treating seizure disorders in a human, wherein the methods and uses comprise orally administering a therapeutically effective amount of the voltage-gated potassium channel allosteric modulator, N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide (Compound A), to the human in need thereof, for example, under fed conditions. The present disclosure is further directed to various improved methods of therapy and administration of Compound A.

1 - 116 . (canceled) 
     
     
         117 . A method of increasing one or more of the C max , AUC inf , T max , or t ½   λz  of Compound A in a human receiving an oral administration of Compound A, comprising orally administering an amount of Compound A to the human under fed conditions;
 wherein Compound A is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide; and   wherein the method increases the one or more of C max , AUC inf , T max , or t ½   λz  as compared to when the same amount of Compound A is orally administered to the human under fasted conditions.   
     
     
         118 . A method of reducing a dose of Compound A that is orally administered to a human in need thereof as part of a treatment regimen, comprising orally administering a reduced amount of Compound A to the human under fed conditions;
 wherein Compound A is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide; and   wherein the reduced amount is a dose lower than would be needed to achieve one or more of the same C max , AUC inf , T max , or t ½   λz  of Compound A when orally administered to the human under fasted conditions.   
     
     
         119 . The method of  claim 118 , wherein the oral administration of Compound A to the human increases one or more of the C max , AUC inf , T max , or t ½   λz  of Compound A as compared to when the same amount of Compound A is orally administered to the human under fasted conditions. 
     
     
         120 . In a method of orally administering Compound A to a human in need thereof, wherein Compound A is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide;
 the improvement comprising orally administering an amount of Compound A to the human under fed conditions.   
     
     
         121 . The method of  claim 120 , wherein the method increases one or more of the C max , AUC inf , T max , or t ½   λz  of Compound A as compared to when the same amount of Compound A is orally administered to the human under fasted conditions. 
     
     
         122 . A method of enhancing opening of a Kv7 potassium channel in a human in need thereof, comprising orally administering an effective amount of Compound A to the human under fed conditions;
 wherein Compound A is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide.   
     
     
         123 . The method of  claim 122 , wherein the human suffers from a seizure disorder. 
     
     
         124 . A method of increasing resting motor threshold (RMT) or active motor threshold (AMT) in a human in need thereof, comprising orally administering an amount of Compound A to the human under fed conditions;
 wherein Compound A is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide; and   wherein the amount of Compound A is sufficient to increase RMT or AMT in the human.   
     
     
         125 . A method of decreasing corticospinal or cortical excitability in a human in need thereof, comprising orally administering an amount of Compound A to the human under fed conditions;
 wherein Compound A is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide; and   wherein the amount of Compound A is sufficient to decrease corticospinal or cortical excitability in the human.   
     
     
         126 . A method of treating a seizure disorder in a human in need thereof, comprising orally administering an amount of Compound A to the human under fed conditions;
 wherein Compound A is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide; and   wherein the amount of Compound A is sufficient to treat the seizure disorder in the human.   
     
     
         127 . The method of  claim 126 , wherein the method increases one or more of the C max , AUC inf , T max , or t ½   λz  of Compound A as compared to when the same amount of Compound A is orally administered to the human under fasted conditions. 
     
     
         128 . The method of  claim 127 , wherein the oral administration of Compound A to the human increases the C. of Compound A as compared to when the same amount of Compound A is orally administered to the human under fasted conditions. 
     
     
         129 . The method of  claim 128 , wherein the increase of the C. of Compound A is at least 50%. 
     
     
         130 . The method of  claim 127 , wherein the oral administration of Compound A to the human increases the AUC inf  of Compound A as compared to when the same amount of Compound A is orally administered to the human under fasted conditions. 
     
     
         131 . The method of  claim 130 , wherein the increase of the AUC inf  of Compound A is at least 50%. 
     
     
         132 . The method of  claim 127 , wherein the oral administration of Compound A to the human increases the T. of Compound A as compared to when the same amount of Compound A is orally administered to the human under fasted conditions. 
     
     
         133 . The method of  claim 132 , wherein the increase of the T max  of Compound A is at least 50%. 
     
     
         134 . The method of  claim 127 , wherein the oral administration of Compound A to the human increases the t ½   λz  of Compound A as compared to when the same amount of Compound A is orally administered to the human under fasted conditions. 
     
     
         135 . The method of  claim 134 , wherein the increase of the t ½   λz  of Compound A is at least 20%. 
     
     
         136 . The method of  claim 126 , wherein the amount of Compound A is from 2 to 200 mg. 
     
     
         137 . The method of  claim 126 , wherein the amount of Compound A is 5-500 mg per day. 
     
     
         138 . The method of  claim 126 , wherein the amount of Compound A is 0.05-2.0 mg/kg. 
     
     
         139 . The method of  claim 126 , wherein the amount of Compound A is administered to the human once-a-day. 
     
     
         140 . The method of  claim 139 , wherein the amount of Compound A is administered using an immediate release formulation comprising Compound A. 
     
     
         141 . The method of  claim 126 , wherein the seizure disorder is focal onset epilepsy. 
     
     
         142 . A kit comprising a plurality of oral dosage unit forms of Compound A and instructions for orally administering the Compound A under fed conditions;
 wherein Compound A is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide.