Claims for Patent: 10,940,141

Summary for Patent: 10,940,141

Title:	Methods for the administration of certain VMAT2 inhibitors
Abstract:	Provided is a method of administering a vesicular monoamine transporter 2 (VMAT2) inhibitor to a subject in need thereof, wherein the subject has severe renal impairment.
Inventor(s):	Loewen; Gordon Raphael (Solana Beach, CA), Luo; Sha Rosa (San Diego, CA)
Assignee:	Neurocrine Biosciences, Inc. (San Diego, CA)
Application Number:	16/989,206
Patent Claims:	1. A method of treating a patient with tardive dyskinesia, comprising: administering a therapeutically effective amount of 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 to the patient, wherein the patient has severe renal impairment, and wherein the therapeutically effective amount is the same amount that would be administered to a patient with normal renal function. 2. The method of claim 1, 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-pyrido[- 2,1-a]isoquinolin-2-yl ester free base once daily. 3. The method of claim 1, wherein the 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. 4. The method of claim 1, wherein the 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. 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 patient has a creatinine clearance of <30 mL/min. 10. The method of claim 1, wherein 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 with severe renal impairment is substantially similar to 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]isoquinol- in-2-yl ester and its active metabolite [+]-.alpha.-HTBZ in the patient with normal renal function. 11. The method of claim 10, wherein the exposure is measured by C.sub.max. 12. The method of claim 10, wherein the exposure is measured by AUC.sub.0-.infin.. 13. The method of claim 1, wherein the VMAT2 inhibitor does not undergo primary renal clearance. 14. A method of treating a patient with tardive dyskinesia, comprising: orally administering 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 to the patient; subsequently determining that the patient has severe renal impairment; and continuing administering the same therapeutically effective amount of the VMAT2 inhibitor to the patient. 15. The method of claim 14, wherein the VMAT2 inhibitor is administered in the form of a tablet or capsule. 16. The method of claim 14, 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. 17. 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. 18. The method of claim 17, 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. 19. The method of claim 14, 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 free base once daily. 20. The method of claim 14, wherein the 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-py- rido[2,1-a]isoquinolin-2-yl ester free base once daily. 21. The method of claim 14, wherein the 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-py- rido[2,1-a]isoquinolin-2-yl ester free base once daily. 22. The method of claim 14, wherein the patient has a creatinine clearance of <30 mL/min. 23. The method of claim 14, wherein 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 with severe renal impairment is substantially similar to 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]isoquinol- in-2-yl ester and its active metabolite [+]-.alpha.-HTBZ in the patient with normal renal function. 24. The method of claim 23, wherein the exposure is measured by C.sub.max. 25. The method of claim 23, wherein the exposure is measured by AUC.sub.0-.infin.. 26. The method of claim 14, wherein the VMAT2 inhibitor does not undergo primary renal clearance. 27. 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; subsequently determining that the patient has severe renal impairment; and continuing administering a therapeutically effective amount of the VMAT2 inhibitor to the patient. 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 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 free base once daily. 30. The method of claim 27, wherein the 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-py- rido[2,1-a]isoquinolin-2-yl ester free base once daily.