Claims for Patent: 10,952,997

Summary for Patent: 10,952,997

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 (+)-a-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]i- soquinolin-2-ol, or a pharmaceutically acceptable salt and/or isotopic variant thereof, to a patient in need thereof wherein the patient is also being administered a strong cytochrome P450 3A4 (CYP3A4) inhibitor.
Inventor(s):	O'Brien; Christopher F. (San Diego, CA), Bozigian; Haig P. (San Diego, CA)
Assignee:	Neurocrine Biosciences, Inc. (San Diego, CA)
Application Number:	16/870,423
Patent Claims:	1. A method of ameliorating one or more symptoms of tardive dyskinesia in a patient, wherein the patient is also being administered a strong cytochrome P450 3A4 (CYP3A4) inhibitor, comprising: orally administering once daily to the patient 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, in an amount 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 strong CYP3A4 inhibitor is chosen from clarithromycin, chloramphenicol, cobicistat, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin. 3. The method of claim 1, wherein the strong CYP3A4 inhibitor is chosen from clarithromycin, itraconazole, and ketoconazole. 4. The method of claim 1, wherein the strong CYP3A4 inhibitor is ketoconazole. 5. The method of claim 1, wherein the VMAT2 inhibitor is administered in the form of a capsule. 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 7, wherein the one or more exposure-related adverse reactions is chosen from somnolence and QT prolongation. 9. The method of claim 7, 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 a pharmaceutically acceptable 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. 12. 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. 13. The method of claim 12, 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. 14. The method of claim 1, wherein the co-administration of the VMAT2 inhibitor and the strong cytochrome P450 3A4 (CYP3A4) inhibitor increases the exposure 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 and its active metabolite, (+)-.alpha.-HTBZ, in the patient, compared to the exposure in a patient who is administered the VMAT2 inhibitor alone. 15. The method of claim 14, wherein the exposure is measured by C.sub.max or AUC.sub.0-.infin.. 16. A method of ameliorating one or more symptoms of tardive dyskinesia in a patient, comprising: (a) orally administering to the patient a 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; (b) subsequently determining that the patient is being administered a strong cytochrome P450 3A4 (CYP3A4) inhibitor; and (c) reducing dosage of the VMAT2 inhibitor administered to the patient to an amount 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 once daily. 17. The method of claim 16, wherein the therapeutically effective amount is an amount equivalent to about 60 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 once daily. 18. The method of claim 16, wherein the therapeutically effective amount is an amount equivalent to about 80 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 once daily. 19. The method of claim 16, wherein the strong CYP3A4 inhibitor is chosen from clarithromycin, itraconazole and ketoconazole. 20. The method of claim 16, wherein the VMAT2 inhibitor is administered in the form of a capsule. 21. The method of claim 16, further comprising monitoring the patient for one or more exposure-related adverse reactions. 22. The method of claim 21, wherein the one or more exposure-related adverse reactions is chosen from somnolence and QT prolongation. 23. The method of claim 21, wherein the one or more exposure-related adverse reactions is QT prolongation. 24. The method of claim 16, 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. 25. The method of claim 16, wherein the co-administration of the VMAT2 inhibitor and the strong cytochrome P450 3A4 (CYP3A4) inhibitor increases the exposure 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 and its active metabolite, (+)-.alpha.-HTBZ, in the patient, compared to the exposure in a patient who is administered the VMAT2 inhibitor alone. 26. A method of ameliorating one or more symptoms of tardive dyskinesia in a patient, comprising: (a) orally administering to the patient a therapeutically effective amount of a vesicular monoamine transporter 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 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 once daily; (b) subsequently determining that the patient is being administered a strong cytochrome P450 3A4 (CYP3A4) inhibitor; and (c) administering the same therapeutically effective amount of the VMAT2 inhibitor to the patient.