Use Of [(1R)-1-(2-Chlorophenyl)-2-(Tetrazol-2-YL)Ethyl] Carbamate In Combination Therapy

Abstract

The present disclosure provides combination therapy using [(1R)-1-(2-chlorophenyl)-2-(tetrazol-2-yl)ethyl] carbamate (cenobamate) and one or more antiepileptic drugs for the prevention or treatment of a neurological disorder such as epilepsy.

What is claimed is: 
     
         1 . A method for treating a patient who is suffering from epilepsy with co-administering a therapeutically effective amount of (i) [(1R)-1-(2-chlorophenyl)-2-(tetrazol-2-yl)ethyl] carbamate (cenobamate) or a pharmaceutically acceptable salt thereof and (ii) one or more antiepileptic drugs, said method comprising:
 modifying the therapeutically effective amount of the antiepileptic drug to adjust AUC of the antiepileptic drug obtained after the co-administration having at least 5% difference to the level of AUC obtained after the administration of antiepileptic drug to the patient without cenobamate or a pharmaceutically acceptable salt thereof,   wherein the therapeutically effective amount of cenobamate or a pharmaceutically acceptable salt thereof is from about 100 mg/day to about 400 mg/day.   
     
     
         2 . The method according to  claim 1 , wherein the antiepileptic drug is selected from the group consisting of carbamazepine, lamotrigine, phenobarbital and phenytoin. 
     
     
         3 . The method according to  claim 1 , wherein the therapeutically effective amount of cenobamate is achieved by the following titration method:
 (1) administering cenobamate to the patient about 12.5 mg once daily for about two weeks;   (2) then administering cenobamate to the patient about 25 mg once daily for two weeks;   (3) then administering cenobamate to the patient about 50 mg once daily for about two weeks; and   (4) then increasing the dose in about bi-weekly increments by no more than about 50 mg once daily to a therapeutically effective amount.   
     
     
         4 . The method according to  claim 1 , wherein the therapeutically effective amount of cenobamate is achieved by the following titration method:
 (1) administering cenobamate to the patient about 50 mg once daily for about two weeks; and   (2) then increasing the dose in about bi-weekly increments by about 50 mg once daily to about 200 mg/day once daily,   wherein cenobamate is administered for about 6 weeks and the therapeutically effective amount of cenobamate is about 200 mg/day.   
     
     
         5 . The method according to  claim 1 , wherein the therapeutically effective amount of cenobamate is achieved by the following titration method:
 (1) administering cenobamate to the patient about 50 mg once daily which is increased with 50 mg once daily per week to about 100 mg/day;   (2) optionally increasing the dose in about weekly increments by about 50 mg once daily per week to about 200 mg/day; and   (3) optionally increasing the dose in about weekly increments by about 100 mg/day per week to about 400 mg/day,   wherein cenobamate is administered for about 2 weeks, 4 weeks, or 6 weeks depending on therapeutically effective amount of cenobamate which is required and the therapeutically effective amount of cenobamate is about 100 mg/day, about 200 mg/day or about 400 mg/day.   
     
     
         6 . The method according to  claim 1 , wherein the antiepileptic drug is carbamazepine. 
     
     
         7 . The method according to  claim 6 , wherein the therapeutically effective amount of carbamazepine is increased by about 5% to about 40% by weight compared to a therapeutically effective amount of the patient in case of its monotherapy. 
     
     
         8 . The method according to  claim 7 , wherein the therapeutically effective amount of carbamazepine is increased by about 11% to about 34% by weight compared to a therapeutically effective amount of the patient in case of its monotherapy. 
     
     
         9 . The method according to  claim 6 , wherein the therapeutically effective amount of carbamazepine is increased to compensate about 5% to about 40% reduction in AUC of carbamazepine obtained after the co-administration to the level of AUC obtained after the administration of carbamazepine to the patient without cenobamate. 
     
     
         10 . The method according to  claim 9 , wherein the therapeutically effective amount of carbamazepine is increased to compensate about 11% to about 34% reduction in AUC of carbamazepine obtained after the co-administration to the level of AUC obtained after the administration of carbamazepine to the patient without cenobamate. 
     
     
         11 . The method according to  claim 1 , wherein the antiepileptic drug is lamotrigine. 
     
     
         12 . The method according to  claim 11 , wherein the therapeutically effective amount of lamotrigine is increased by about 7% to about 140% by weight compared to a therapeutically effective amount of the patient in case of its monotherapy. 
     
     
         13 . The method according to  claim 12 , wherein the therapeutically effective amount of lamotrigine is increased by about 18% to about 93% by weight compared to a therapeutically effective amount of the patient in case of its monotherapy. 
     
     
         14 . The method according to  claim 11 , wherein the therapeutically effective amount of lamotrigine is increased to compensate about 10% to about 60% reduction in AUC of lamotrigine obtained after the co-administration to the level of AUC obtained after the administration of lamotrigine to the patient without cenobamate. 
     
     
         15 . The method according to  claim 14 , wherein the therapeutically effective amount of lamotrigine is increased to compensate about 21% to about 52% reduction in AUC of lamotrigine obtained after the co-administration to the level of AUC obtained after the administration of lamotrigine to the patient without cenobamate. 
     
     
         16 . The method according to  claim 1 , wherein the antiepileptic drug is phenobarbital. 
     
     
         17 . The method according to  claim 16 , wherein the therapeutically effective amount of phenobarbital is decreased by about 20% to about 50% by weight compared to a therapeutically effective amount of the patient in case of its monotherapy. 
     
     
         18 . The method according to  claim 17 , wherein the therapeutically effective amount of phenobarbital is decreased by about 25% to about 45% by weight compared to a therapeutically effective amount of the patient in case of its monotherapy. 
     
     
         19 . The method according to  claim 16 , wherein the therapeutically effective amount of phenobarbital is decreased to adjust about 20% to about 50% increase in AUC of phenobarbital obtained after the co-administration to the level of AUC obtained after the administration of phenobarbital to the patient without cenobamate. 
     
     
         20 . The method according to  claim 19 , wherein the therapeutically effective amount of phenobarbital is decreased to adjust about 25% to about 45% increase in AUC of phenobarbital obtained after the co-administration to the level of AUC obtained after the administration of phenobarbital to the patient without cenobamate. 
     
     
         21 . The method according to  claim 1 , wherein the antiepileptic drug is phenytoin. 
     
     
         22 . The method according to  claim 21 , wherein the therapeutically effective amount of phenytoin is decreased by about 7% to about 55% by weight compared to a therapeutically effective amount of the patient in case of its monotherapy. 
     
     
         23 . The method according to  claim 22 , wherein the therapeutically effective amount of phenytoin is decreased by about 10% to about 40% by weight compared to a therapeutically effective amount of the patient in case of its monotherapy. 
     
     
         24 . The method according to  claim 21 , wherein the therapeutically effective amount of phenytoin is decreased to adjust about 10% to about 100% increase in AUC of phenytoin obtained after the co-administration to the level of AUC obtained after the administration of phenytoin to the patient without cenobamate. 
     
     
         25 . The method according to  claim 24 , wherein the therapeutically effective amount of phenytoin is decreased to adjust about 10% to about 60% increase in AUC of phenytoin obtained after the co-administration to the level of AUC obtained after the administration of phenytoin to the patient without cenobamate. 
     
     
         26 . A method for treating a patient who is suffering from epilepsy with co-administering a therapeutically effective amount of (i) [(1R)-1-(2-chlorophenyl)-2-(tetrazol-2-yl)ethyl] carbamate (cenobamate) or a pharmaceutically acceptable salt thereof and (ii) phenytoin, said method comprising:
 increasing the therapeutically effective amount of cenobamate to compensate about 20% to about 40% reduction in AUC of cenobamate obtained after the co-administration to the level of AUC obtained after the administration of cenobamate to the patient without phenytoin.   
     
     
         27 . The method according to  claim 26 , cenobamate or a pharmaceutically acceptable salt thereof is administered to the patient with the following titration method:
 (1) administering cenobamate to the patient about 12.5 mg once daily for about two weeks;   (2) then administering cenobamate to the patient about 25 mg once daily for two weeks;   (3) then administering cenobamate to the patient about 50 mg once daily for about two weeks; and   (4) then increasing the dose in about bi-weekly increments by no more than about 50 mg once daily to a therapeutically effective amount.   
     
     
         28 . The method according to  claim 26 , wherein the therapeutically effective amount of cenobamate is achieved by the following titration method:
 (1) administering cenobamate to the patient about 50 mg once daily for about two weeks; and   (2) then increasing the dose in about bi-weekly increments by about 50 mg once daily to about 200 mg/day once daily,   wherein cenobamate is administered for about 6 weeks and the therapeutically effective amount of cenobamate is about 200 mg/day.   
     
     
         29 . The method according to  claim 26 , wherein the therapeutically effective amount of cenobamate is achieved by the following titration method:
 (1) administering cenobamate to the patient about 50 mg once daily which is increased with 50 mg once daily per week to about 100 mg/day;   (2) optionally increasing the dose in about weekly increments by about 50 mg once daily per week to about 200 mg/day; and   (3) optionally increasing the dose in about weekly increments by about 100 mg/day per week to about 400 mg/day,   wherein cenobamate is administered for about 2 weeks, 4 weeks, or 6 weeks depending on therapeutically effective amount of cenobamate which is required and the therapeutically effective amount of cenobamate is about 100 mg/day, about 200 mg/day or about 400 mg/day.   
     
     
         30 . The method according to  claim 26 , the therapeutically effective amount of cenobamate or a pharmaceutically acceptable salt thereof is ranging from about 100 mg/day to about 400 mg/day. 
     
     
         31 . The method according to  claim 26 , wherein the therapeutically effective amount of cenobamate is increased by about 50% by weight compared to its therapeutically effective amount of the patient in case of its monotherapy. 
     
     
         32 . The method according to  claim 26 , wherein the therapeutically effective amount of cenobamate is increased to compensate about 25% to about 35% reduction in AUC of cenobamate obtained after the co-administration to the level of AUC obtained after the administration of cenobamate to the patient without phenytoin.