Claims for Patent: 10,993,941

Summary for Patent: 10,993,941

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 has mild, moderate, or severe hepatic impairment.
Inventor(s):	O'Brien; Christopher F. (San Diego, CA), Bozigian; Haig P. (San Diego, CA)
Assignee:	Neurocrine Biosciences, Inc. (San Diego, CA)
Application Number:	16/870,823
Patent Claims:	1. A method of ameliorating one or more symptoms of tardive dyskinesia in a patient, wherein the patient has moderate or severe hepatic impairment, comprising: administering 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-py- rido[2,1-a]isoquinolin-2-yl ester and pharmaceutically acceptable salts thereof, wherein the VMAT2 inhibitor is administered 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 once daily. 2. The method of claim 1, wherein the patient has moderate hepatic impairment. 3. The method of claim 1, wherein the patient has severe hepatic impairment. 4. The method of claim 1, wherein the VMAT2 inhibitor is administered orally. 5. The method of claim 1, wherein the VMAT2 inhibitor is administered in the form of a 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 6, 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 patient has a Child-Pugh Score of 7-9 or 10-15. 10. The method of claim 1, wherein the patient with moderate to severe hepatic impairment has higher 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-py- rido[2,1-a]isoquinolin-2-yl ester and its active metabolite, (+)-.alpha.-HTBZ, than the exposure in a patient with normal hepatic function who is administered the same amount of the VMAT2 inhibitor. 11. The method of claim 10, wherein the exposure is measured by C.sub.max or AUC.sub.0-.infin.. 12. A method of treating a patient 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-py- rido[2,1-a]isoquinolin-2-yl ester and pharmaceutically acceptable salts thereof, (b) subsequently determining that the patient has moderate or severe hepatic impairment; 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. 13. The method of claim 12, wherein the patient has moderate hepatic impairment. 14. The method of claim 12, wherein the patient has severe hepatic impairment. 15. The method of claim 12, wherein the patient has a Child-Pugh Score of 7-9 or 10-15. 16. The method of claim 12, wherein the VMAT2 inhibitor is administered in the form of a tablet or capsule. 17. The method of claim 12, 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. 18. The method of claim 17, 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. 19. The method of claim 12, wherein the patient has higher 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, than the exposure in a patient with normal hepatic function who is administered the same amount of the VMAT2 inhibitor. 20. The method of claim 19, wherein the exposure is measured by C.sub.max. 21. The method of claim 20, wherein the exposure is measured by AUC.sub.0-.infin.. 22. The method of claim 12, 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. 23. The method of claim 12, 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. 24. A method of treating a patient ameliorating one or more symptoms of tardive dyskinesia in a patient, comprising: determining the hepatic function of the patient; and if the patient has moderate or severe hepatic impairment, orally administering to the patient 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, wherein the first therapeutically effective amount is 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; or if the patient has mild hepatic impairment or normal hepatic function, orally administering to the patient a second 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, wherein the second therapeutically effective amount is 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 for one week, and subsequently administering an increased amount of the VMAT2 inhibitor after one week. 25. The method of claim 24, wherein the hepatic function is determined by Child-Pugh scale. 26. The method of claim 24, wherein the patient with mild hepatic impairment has a Child-Pugh score of 5-6; the patient with moderate hepatic impairment has a Child-Pugh score of 7-9; and the patient with severe hepatic impairment has a Child-Pugh score of 10-15. 27. The method of claim 24, wherein the increased amount is an amount equivalent to about 80 mg as measured by (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyr- ido[2,1-a]isoquinolin-2-yl ester once daily. 28. The method of claim 24, 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. 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 of (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 once daily; (b) subsequently determining that the patient has moderate or severe hepatic impairment; and (C) administering the same therapeutically effective amount of the VMAT2 inhibitor to the patient.