Claims for Patent: 10,857,137

Summary for Patent: 10,857,137

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 and (+)-.alpha.-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2- ,1-a]isoquinolin-2-ol, or a pharmaceutically acceptable salt and/or isotopic variant thereof, to a patient in need thereof wherein the patient is a CYP2D6 poor metabolizer.
Inventor(s):	O'Brien; Christopher F. (San Diego, CA), Bozigian; Haig P. (San Diego, CA)
Assignee:	Neurocrine Biosciences, Inc. (San Diego, CA)
Application Number:	16/870,706
Patent Claims:	1. A method of treating a patient with tardive dyskinesia, wherein the patient is a cytochrome P450 2D6 (CYP2D6) poor metabolizer, comprising: orally administering once daily to the patient a vesicular monoamine transport 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-py- rido[2,1-a]isoquinolin-2-yl ester and pharmaceutically acceptable salts thereof, in an amount of equivalent to about 40 mg as measured by (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. 2. The method of claim 1, wherein the patient has a CYP2D6 poor metabolizer genotype. 3. The method of claim 2, wherein the CYP2D6 poor metabolizer genotype is CYP2D6G1846A genotype or CYP2D6C100T genotype. 4. The method of claim 2, wherein the CYP2D6 poor metabolizer genotype is CYP2D6G1846A (AA) genotype. 5. The method of claim 2, wherein the CYP2D6 poor metabolizer genotype is CYP2D6C100T (TT) genotype or CYP2D6C100T (CT) genotype. 6. The method of claim 1, further comprising monitoring the patient for one or more exposure-related adverse reactions. 7. The method of claim 6, wherein the one or more exposure-related adverse reactions is chosen from somnolence, anticholinergic effects, balance disorders or falls, headache, akathisia, vomiting, nausea, arthralgia, QT prolongation, increase in blood glucose, increase in weight, respiratory infections, drooling, dyskinesia, extrapyramidal symptoms (non-akathisia), anxiety, insomnia, increase in prolactin, increase in alkaline phosphatase, and increase in bilirubin. 8. The method of claim 6, wherein the one or more exposure-related adverse reactions is chosen from somnolence and QT prolongation. 9. The method of claim 6, wherein the one or more exposure-related adverse reactions is QT prolongation. 10. The method of claim 1, wherein the VMAT2 inhibitor is administered with or without food. 11. The method of claim 1, wherein the VMAT2 inhibitor is administered in the form of a capsule. 12. The method of claim 1, wherein the VMAT2 inhibitor is a tosylate 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. 13. The method of claim 1, 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. 14. The method of claim 13, 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. 15. The method of claim 1, wherein the patient who is a CYP2D6 poor metabolizer has an increased exposure to the active metabolite 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 compared with the patient who is not a poor CYP2D6 metabolizer when both patients are administered the same amount of the VMAT2 inhibitor. 16. The method of claim 15, wherein the exposure is measured by C.sub.max or AUC.sub.0-.infin.. 17. A method of treating a patient with tardive dyskinesia, comprising: (a) orally administering to the patient a therapeutically effective amount of a vesicular monoamine transport 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; (b) subsequently determining that the patient is a cytochrome P450 2D6 (CYP2D6) poor metabolizer; and (c) reducing dosage of the VMAT2 inhibitor administered to the patient to an amount equivalent to about 40 mg once daily as measured by (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. 18. The method of claim 15, wherein the therapeutically effective amount is an amount equivalent to about 60 mg once daily as measured by (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. 19. The method of claim 17, wherein the therapeutically effective amount is an amount equivalent to about 80 mg once daily as measured by (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. 20. The method of claim 17, wherein the patient has CYP2D6G1846A (AA) genotype. 21. The method of claim 17, wherein the patient has CYP2D6C100T (TT) genotype or CYP2D6C100T (CT) genotype. 22. The method of claim 17, further comprising monitoring the patient for one or more exposure-related adverse reactions. 23. The method of claim 22, wherein the one or more exposure-related adverse reactions is QT prolongation. 24. The method of claim 17, wherein the VMAT2 inhibitor is a ditosylate salt of (5)-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-c]isoquinolin-2-yl ester. 25. The method of claim 17, wherein the patient who is a CYP2D6 poor metabolizer has an increased exposure to the active metabolite 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 compared with the patient who is not a poor CYP2D6 metabolizer when both patients are administered the same amount of the VMAT2 inhibitor. 26. The method of claim 25, wherein the exposure is measured by C.sub.max or AUC.sub.0-.infin.. 27. A method of treating a patient with tardive dyskinesia, comprising: determining if the patient is a poor metabolizer of cytochrome P450 2D6 (CYP2D6); and if the patient is a poor metabolizer of cytochrome P450 2D6 (CYP2D6), then orally administering to the patient a first therapeutically effective amount of a vesicular monoamine transport 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, wherein the first therapeutically effective amount is an amount equivalent to about 40 mg once daily as measured by (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; or if the patient is not a poor metabolizer of cytochrome P450 2D6 (CYP2D6), then orally administering to the patient a second therapeutically effective amount of a vesicular monoamine transport 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-py- rido[2,1-a]isoquinolin-2-yl ester and pharmaceutically acceptable salts thereof, wherein the second therapeutically effective amount is an amount equivalent to about 40 mg once daily as measured by (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 for one week, and subsequently administering an increased amount of the VMAT2 inhibitor after one week. 28. The method of claim 27, 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. 29. The method of claim 27, wherein the increased amount is an amount equivalent to about 80 mg once daily as measured by (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. 30. A method of treating a patient with tardive dyskinesia, comprising: (a) orally administering to the patient a therapeutically effective amount of a vesicular monoamine transport 2 (VMAT2) inhibitor which 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, wherein the therapeutically effective amount is an amount equivalent to about 40 mg once daily as measured by (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; (b) subsequently determining that the patient is a poor metabolizer of cytochrome P450 2D6 (CYP2D6); and (c) administering the same therapeutically effective amount of the VMAT2 inhibitor to the patient.