Methods of use of T-type calcium channel modulators
Described herein, in part, are methods useful for preventing and/or treating a disease or condition relating to aberrant function or activity of a T-type calcium channel, such as psychiatric disorders (e.g., mood disorder (e.g., major depressive disorder)), pain, tremor (e.g., essential tremor), seizures (e.g., absence seizures), epilepsy, or an epilepsy syndrome (e.g., juvenile myoclonic epilepsy). The present invention further comprises methods for modulating the function of a T-type calcium channel and methods of administering a titrated dosage of a T-type calcium channel antagonist.
1 . A method of treating a subject suffering from essential tremor, the method comprising administering to said subject a titrated dose of a compound of formula (I):
or a pharmaceutically acceptable salt thereof, wherein administering the titrated dose of the compound of formula (I), or a pharmaceutically acceptable salt thereof, comprises:
(a) administering to said subject a first dose of the compound of formula (I), or a pharmaceutically acceptable salt thereof, of about 5 mg to about 40 mg per day for a first period of time;
(b) administering to said subject one or more increased doses of the compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein the one or more increased doses are increased relative to the first dose, to arrive at a maximum titrated dose of about 20 mg to about 120 mg per day; and
(c) administering the maximum titrated dose of the compound of formula (I), or a pharmaceutically acceptable salt thereof, to the subject.
2 . The method of claim 1 , wherein the first period of time is 3 days.
3 . The method of claim 1 , wherein in step (b), the one or more increased doses of the compound of formula (I), or a pharmaceutically acceptable salt thereof, are administered to the subject for a period of time ranging from 3 days to 7 days.
4 . The method of claim 1 , wherein in the first period of time, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered at a dose of about 20 mg to about 40 mg per day.
5 . The method of claim 1 , wherein step (b) comprises:
(i) increasing the first dose to a second dose and administering the second dose of the compound of formula (I), or a pharmaceutically acceptable salt thereof, to the subject for a second period of time, wherein the second dose is about 40 mg to about 80 mg per day; or
(ii) increasing the first dose to a second dose and administering the second dose of the compound of formula (I), or a pharmaceutically acceptable salt thereof, to the subject for a second period of time, wherein the second dose is about 40 mg to about 60 mg per day; and
increasing the second dose to a third dose and administering the third dose of the compound of formula (I), or a pharmaceutically acceptable salt thereof, to the subject for a third period of time, wherein the third dose is about 80 mg to about 100 mg per day.
6 . The method of claim 5 , wherein (ii) further comprises increasing the third dose to a fourth dose and administering the fourth dose of the compound of formula (I), or a pharmaceutically acceptable salt thereof, to the subject for a fourth period of time, wherein the fourth dose is about 120 mg per day; or wherein in (ii) the third dose is about 80 mg per day.
7 . The method of claim 1 , wherein the the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered at a first dose of about 20 mg per day, and wherein step (b) comprises increasing the first dose to a second dose of about 40 mg per day and administering the second dose of the compound of formula (I), or a pharmaceutically acceptable salt thereof, to the subject for a second period of time.
8 . The method of claim 7 , wherein the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered at a second dose of about 40 mg per day, and wherein step (b) further comprises:
increasing the second dose to a third dose of about 60 mg per day and administering the third dose of the compound for formula (I), or a pharmaceutically acceptable salt thereof, to the subject for a third period of time.
9 . The method of claim 1 , wherein the pharmaceutically acceptable salt of the compound of formula (I) is a hydrochloride salt of formula (II):
10 . The method of claim 1 , wherein the compound of formula (I), or a pharmaceutically acceptable salt thereof, is in a modified release dosage formulation comprising at least one modified release polymer.
11 . The method of claim 10 , wherein about 80% of the compound of formula (I), or a pharmaceutically acceptable salt thereof, is released within 7 hours upon administration to the subject.
12 . The method of claim 10 , wherein the modified release polymer is hydroxypropyl methylcellulose, ethylcellulose, or a polyacrylate polymer.
13 . The method of claim 12 , wherein the modified release polymer is hydroxypropyl methylcellulose.
14 . The method of claim 1 , wherein the method results in an EEG sigma frequency band reduction during NREM sleep in the subject.
15 . The method of claim 14 , wherein a ratio of the EEG sigma frequency band reduction to an EEG sigma frequency band baseline during NREM sleep in the subject ranges from about 0.4 to about 0.7.
16 . The method of claim 1 , wherein the first period of time is 3 days to 9 days.
17 . The method of claim 16 , wherein the first period of time is 7 days.
18 . The method of claim 1 , wherein the second period of time is 3 days to 9 days.
19 . The method of claim 18 , wherein the second period of time is 7 days.
20 . The method of claim 1 , wherein administering the titrated dose of the compound of formula (I), or a pharmaceutically acceptable salt thereof, comprises:
(a) administering to the subject a first dose of the compound of formula (I), or a pharmaceutically acceptable salt thereof, of about 20 mg to about 40 mg per day for a first period of time;
(b) administering to the subject a second dose of the compound of formula (I), or a pharmaceutically acceptable salt thereof, of about 40 mg to about 80 mg per day for a second period of time; and
(c) administering to the subject a third dose of the compound of formula (I), or a pharmaceutically acceptable salt thereof, of about 60 mg to about 120 mg for a third period of time.
21 . The method of claim 20 , wherein the first dose is about 20 mg per day or 40 mg per day.
22 . The method of claim 21 , wherein the first dose is about 20 mg per day.
23 . The method of claim 20 , wherein the second dose is about 40 mg per day, about 60 mg per day or about 80 mg per day.
24 . The method of claim 23 , wherein the second dose is about 40 mg per day.
25 . The method of claim 20 , wherein the third dose is about 60 mg per day, about 80 mg per day, about 100 mg per day or about 120 mg per day.
26 . The method of claim 25 , wherein the third dose is about 60 mg per day.
27 . The method of claim 20 , wherein the third period of time is 3 days to 9 days.
28 . The method of claim 27 , wherein the third period of time is 7 days.
29 . The method of claim 8 , wherein step (b) further comprises increasing the third dose to a fourth dose of about 80 mg per day and administering the fourth dose of the compound of formula (I), or a pharmaceutically acceptable salt thereof, to the subject for a fourth period of time.
30 . The method of claim 29 , wherein step (b) further comprises increasing the fourth dose to a fifth dose of about 100 mg per day and administering the fifth dose of the compound of formula (I), or a pharmaceutically acceptable salt thereof, to the subject for a fifth period of time,
wherein the maximum titrated dose of the compound of formula (I), or a pharmaceutically acceptable salt thereof, is about 120 mg per day.