Methods of using radiprodil in the treatment of disorders
The present disclosure provides, in part, methods of treating an epileptic disorder in a pediatric subject in need thereof, comprising administering radiprodil to the pediatric subject; pharmaceutical compositions comprising radiprodil and pharmaceutically acceptable excipients and methods of use thereof in the treatment of disorders such as epileptic disorders.
1 . A method of treating a GRIN-related neurodevelopmental disorder in a subject in need thereof, the method comprising orally administering to the subject a pharmaceutical composition comprising: (i) an anhydrous crystalline form of a compound of Formula I:
wherein the anhydrous crystalline form (Form A) has an X-ray powder diffraction pattern with characteristic peaks between and including the following values of 2θ in degrees: 7.8, 22.0, 23.7, 27.0 and 27.6±0.2° 2 θ, and (ii) a pharmaceutically acceptable excipient;
wherein orally administering comprises:
(i) a titration dose comprising:
orally administering the pharmaceutical composition to the subject in an amount sufficient to provide the subject 0.05 mg/kg to about 1.0 mg/kg of the compound twice a day;
and
(ii) a maintenance dose comprising:
orally administering the pharmaceutical composition to the subject in an amount sufficient to provide the subject about 0.5 mg/kg to about 1.0 mg/kg of the compound twice a day.
2 . The method of claim 1 , wherein the subject is a pediatric subject.
3 . The method of claim 1 , wherein the subject is suffering from tuberous sclerosis complex.
4 . The method of claim 1 , wherein the subject is suffering from focal cortical dysplasia.
5 . The method of claim 1 , wherein the subject has been identified as having a GRIN mutation.
6 . The method of claim 5 , wherein the mutation is a GRIN2A gain-of-function mutation, a GRIN2B gain-of-function mutation, a GRIN1 gain-of-function mutation, or a GRIN2D gain-of-function mutation.
7 . The method of claim 1 , wherein the compound is orally administered to the subject within one to four hours of the subject eating food.
8 . The method of claim 7 , wherein the compound is orally administered to the subject within one to four hours of the subject eating a high-fat meal.
9 . The method of claim 7 , wherein the compound is orally administered to the subject within two hours of the subject eating food.
10 . The method of claim 1 , wherein the pharmaceutical composition comprises: about 30% by weight of the anhydrous crystalline form of the compound based on the total weight of the pharmaceutical composition.
11 . The method of claim 1 , wherein the titration dose comprises:
orally administering the pharmaceutical composition to the subject in an amount sufficient to provide the subject 0.125 mg/kg to 1.0 mg/kg twice a day.
12 . The method of claim 1 , wherein the titration dose comprises:
orally administering the pharmaceutical composition to the subject in an amount sufficient to provide the subject 0.125 mg/kg to 0.75 mg/kg twice a day.
13 . The method of claim 1 , wherein the maintenance dose comprises:
orally administering the pharmaceutical composition to the subject in an amount sufficient to provide the subject 1.0 mg/kg of the compound twice a day.
14 . The method of claim 1 , wherein the maintenance dose comprises:
orally administering the pharmaceutical composition to the subject in an amount sufficient to provide the subject 0.75 mg/kg of the compound twice a day.
15 . The method of claim 12 , wherein the maintenance dose comprises:
orally administering the pharmaceutical composition to the subject in an amount sufficient to provide the subject 0.75 mg/kg of the compound twice a day.
16 . A method of treating a subject with a GRIN-related neurodevelopmental disorder, the method comprising administering to the subject a pharmaceutical composition comprising:
(i) an anhydrous crystalline form of a compound of Formula I:
wherein the anhydrous crystalline form (Form A) has an X-ray powder diffraction pattern with characteristic peaks between and including the following values of 2θ in degrees: 7.8, 22.0, 23.7, 27.0 and 27.6±0.2° 2 θ, and (ii) a pharmaceutically acceptable excipient,
wherein the composition is orally administered to the subject, within four hours of eating food, in an amount sufficient to provide a titration dose of the compound twice a day followed by a maintenance dose of the compound twice a day; wherein:
the titration dose is 0.05 mg/kg to about 0.75 mg/kg of the compound; and
the maintenance dose is about 0.75 mg/kg of the compound.
17 . The method of claim 16 , wherein the compound is orally administered to the subject within two hours of the subject eating food.
18 . The method of claim 16 , wherein the subject has been identified as having a GRIN mutation.
19 . The method of claim 16 , wherein the subject is a pediatric subject.
20 . The method of claim 16 , wherein the titration dose is 0.125 mg/kg to 0.75 mg/kg of the compound.
21 . The method of claim 20 , wherein the maintenance dose is 0.75 mg/kg of the compound.
22 . The method of claim 16 , wherein the pharmaceutical composition comprises: about 30% by weight of the anhydrous crystalline form of the compound based on the total weight of the pharmaceutical composition.
23 . A method of treating a GRIN-related neurodevelopmental disorder in a subject in need thereof, the method comprising orally administering to the subject a pharmaceutical composition comprising: (i) an anhydrous crystalline form of a compound of Formula I:
wherein the anhydrous crystalline form (Form A) has an X-ray powder diffraction pattern with characteristic peaks between and including the following values of 2θ in degrees: 7.8, 22.0, 23.7, 27.0 and 27.6±0.2° 2 θ, and (ii) a pharmaceutically acceptable excipient;
wherein the composition is orally administered to the subject within one to four hours of the subject eating food,
wherein orally administering comprises:
(iii) a titration dose comprising:
orally administering the pharmaceutical composition to the subject in an amount sufficient to provide the subject 0.05 mg/kg to about 1.0 mg/kg of the compound twice a day;
and
(iv) a maintenance dose comprising:
orally administering the pharmaceutical composition to the subject in an amount sufficient to provide the subject about 0.5 mg/kg to about 1.0 mg/kg of the compound twice a day.
24 . The method of claim 23 , wherein the subject has been identified as having a GRIN mutation.
25 . The method of claim 24 , wherein the mutation is a GRIN2A gain-of-function mutation, a GRIN2B gain-of-function mutation, a GRIN1 gain-of-function mutation, or a GRIN2D gain-of-function mutation.
26 . The method of claim 23 , wherein the subject is a pediatric subject.
27 . A method of treating a subject with a GRIN-related neurodevelopmental disorder, the method comprising administering to the subject a pharmaceutical composition comprising:
(i) an anhydrous crystalline form of a compound of Formula I:
wherein the anhydrous crystalline form (Form A) has an X-ray powder diffraction pattern with characteristic peaks between and including the following values of 2θ in degrees: 7.8, 22.0, 23.7, 27.0 and 27.6±0.2° 2 θ, and (ii) a pharmaceutically acceptable excipient,
wherein the composition comprises about 30% by weight of the anhydrous crystalline form of the compound based on the total weight of the pharmaceutical composition, and
wherein the composition is orally administered to the subject in an amount sufficient to provide a titration dose of the compound twice a day followed by a maintenance dose of the compound twice a day; wherein:
the titration dose is about 0.05 mg/kg to about 1 mg/kg of the compound.
28 . The method of claim 27 , wherein the subject is a pediatric subject.
29 . The method of claim 27 , wherein the subject has been identified as having a GRIN mutation.
30 . The method of claim 29 , wherein the mutation is a GRIN2A gain-of-function mutation, a GRIN2B gain-of-function mutation, a GRIN1 gain-of-function mutation, or a GRIN2D gain-of-function mutation.