Claims for Patent: 11,026,931

Summary for Patent: 11,026,931

Title:	Methods for the administration of certain VMAT2 inhibitors
Abstract:	Provided are methods of administering a vesicular monoamine transport 2 (VMAT2) inhibitor chosen from valbenazine, or a pharmaceutically acceptable salt and/or isotopic variant thereof, to a patient in need thereof.
Inventor(s):	Liang; Grace S. (San Diego, CA), O'Brien; Christopher F. (Vashon, WA), Thai-Cuarto; Dao Tuyet (San Diego, CA)
Assignee:	Neurocrine Biosciences, Inc. (San Diego, CA)
Application Number:	16/983,334
Patent Claims:	1. A method of treating a patient with tardive dyskinesia, comprising: administering a vesicular monoamine transporter 2 (VMAT2) inhibitor chosen from (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[- 2,1-a]isoquinolin-2-yl ester and pharmaceutically acceptable salts thereof to the patient, wherein the VMAT2 inhibitor is administered in an amount equivalent to about 40 mg, about 60 mg, or about 80 mg of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[- 2,1-a]isoquinolin-2-yl ester free base once daily; monitoring the patient for one or more exposure-related adverse reactions; and discontinuing administration of the VMAT2 inhibitor based on the patient's ability to tolerate one or more exposure-related adverse reactions; wherein the one or more exposure-related adverse reactions is selected from hypersensitivity reactions. 2. The method of claim 1, wherein the amount of the VMAT2 inhibitor is an amount equivalent to about 40 mg of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[- 2,1-a]isoquinolin-2-yl ester free base once daily. 3. The method of claim 1, wherein the amount of the VMAT2 inhibitor is an amount equivalent to about 60 mg of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3 sobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoli- n-2-yl ester free base once daily. 4. The method of claim 1, wherein the amount of the VMAT2 inhibitor is an amount equivalent to about 80 mg of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[- 2,1-a]isoquinolin-2-yl ester free base once daily. 5. The method of claim 1, wherein the VMAT2 inhibitor is administered in the form of a tablet or capsule. 6. The method of claim 1, wherein the VMAT2 inhibitor is a salt of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[- 2,1-a]isoquinolin-2-yl ester. 7. The method of claim 6, wherein the VMAT2 inhibitor is a ditosylate salt of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[- 2,1-a]isoquinolin-2-yl ester. 8. The method of claim 7, wherein the ditosylate salt of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[- 2,1-a]isoquinolin-2-yl ester is in polymorphic Form I. 9. The method of claim 1, wherein the one or more exposure-related adverse reactions is hypersensitivity. 10. The method of claim 9, wherein the hypersensitivity is selected from allergic dermatitis, angioedema, pruritis, and urticaria. 11. A method of treating a patient with tardive dyskinesia, comprising: orally administering a first therapeutically effective amount of a vesicular monoamine transporter 2 (VMAT2) inhibitor chosen from (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[- 2,1-a]isoquinolin-2-yl ester and pharmaceutically acceptable salts thereof to the patient; monitoring the patient for the presence or absence of one or more exposure-related adverse reactions; if the one or more exposure-related adverse reactions is present, discontinuing administration of the VMAT2 inhibitor; and if the one or more exposure-related adverse reactions is absent, continuing administering a second therapeutically effective amount of the vesicular monoamine transporter 2 (VMAT2) inhibitor to the patient; wherein the one or more exposure-related adverse reactions is selected from hypersensitivity reactions, and wherein the second therapeutically effective amount is the same amount or an increased amount compared to the first therapeutically effective amount. 12. The method of claim 11, wherein the VMAT2 inhibitor is administered in the form of a tablet or capsule. 13. The method of claim 11, wherein the VMAT2 inhibitor is a salt of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[- 2,1-a]isoquinolin-2-yl ester. 14. The method of claim 11, wherein the VMAT2 inhibitor is a ditosylate salt of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[- 2,1-a]isoquinolin-2-yl ester. 15. The method of claim 14, wherein the ditosylate salt of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[- 2,1-a]isoquinolin-2-yl ester is in polymorphic Form I. 16. The method of claim 11, wherein the first therapeutically effective amount is an amount equivalent to about 40 mg, of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3 sobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoli- n-2-yl ester free base once daily. 17. The method of claim 11, wherein the first therapeutically effective amount is an amount equivalent to about 60 mg of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3 sobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoli- n-2-yl ester free base once daily. 18. The method of claim 11, wherein the first therapeutically effective amount is an amount equivalent to about 80 mg of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[- 2,1-a]isoquinolin-2-yl ester free base once daily. 19. The method of claim 11, wherein the second therapeutically effective amount is an amount equivalent to about 40 mg of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[- 2,1-a]isoquinolin-2-yl ester free base once daily. 20. The method of claim 11, wherein the second therapeutically effective amount is an amount equivalent to about 60 mg of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[- 2,1-a]isoquinolin-2-yl ester free base once daily. 21. The method of claim 11, wherein the second therapeutically effective amount is an amount equivalent to about 80 mg of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[- 2,1-a]isoquinolin-2-yl ester free base once daily. 22. The method of claim 11, wherein the hypersensitivity reactions are selected from allergic dermatitis, angioedema, pruritis, and urticaria. 23. A method of treating a patient with tardive dyskinesia, comprising: administering a vesicular monoamine transporter 2 (VMAT2) inhibitor chosen from (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[- 2,1-a]isoquinolin-2-yl ester and pharmaceutically acceptable salts thereof to the patient, wherein the patient is administered an initial dose of the VMAT2 inhibitor in an amount equivalent to about 40 mg of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[- 2,1-a]isoquinolin-2-yl ester free base once daily for one week, and an amount equivalent to about 80 mg of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[- 2,1-a]isoquinolin-2-yl ester free base once daily after one week; monitoring the patient for one or more exposure-related adverse reactions; and discontinuing administration of the VMAT2 inhibitor based on the patient's ability to tolerate one or more exposure-related adverse reactions; wherein the one or more exposure-related adverse reactions is selected from hypersensitivity reactions. 24. The method of claim 23, wherein the VMAT2 inhibitor is a salt of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[- 2,1-a]isoquinolin-2-yl ester. 25. The method of claim 23, wherein the VMAT2 inhibitor is a ditosylate salt of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[- 2,1-a]isoquinolin-2-yl ester. 26. The method of claim 25, wherein the ditosylate salt of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[- 2,1-a]isoquinolin-2-yl ester is in polymorphic Form I. 27. The method of claim 23, wherein the hypersensitivity reactions are selected from allergic dermatitis, angioedema, pruritis, and urticaria. 28. The method of claim 9, wherein the hypersensitivity is angioedema. 29. The method of claim 9, wherein the hypersensitivity is pruritis. 30. The method of claim 9, wherein the hypersensitivity is urticaria.