Claims for Patent: 10,857,148

Summary for Patent: 10,857,148

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 also being administered digoxin.
Inventor(s):	O'Brien; Christopher F. (San Diego, CA), Bozigian; Haig P. (San Diego, CA)
Assignee:	Neurocrine Biosciences, Inc. (San Deigo, CA)
Application Number:	16/871,528
Patent Claims:	1. A method for treating a patient with tardive dyskinesia, wherein the patient is also being co-administered digoxin, comprising: (a) 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 sobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoli- n-2-yl ester, (+)-.alpha.-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2- ,1-a]isoquinolin-2-ol, and pharmaceutically acceptable salts and isotopic variants thereof, (b) monitoring the digoxin concentration in the patient's blood; and (c) reducing the dose of digoxin when the digoxin exposure in the patient's blood is increased as compared with the digoxin level in a patient who is administered digoxin alone. 2. The method of claim 1, wherein the digoxin exposure is measured as the area under the plasma concentration versus time curve from 0 hours extrapolated to infinity or measured as the maximum observed blood plasma concentration (C.sub.max) at the time of maximum plasma concentration (t.sub.max). 3. The method of claim 1, wherein the increased digoxin exposure increases the risk of one or more exposure-related adverse reactions. 4. The method of claim 3, further comprising monitoring the patient for one or more exposure-related adverse reactions. 5. The method of claim 4, wherein the one or more exposure-related adverse reactions is selected from headache, anxiety, insomnia, diarrhea, restlessness, and abnormal dreams. 6. The method of claim 1, further comprising obtaining a baseline serum digoxin concentration prior to administering to the patient the therapeutically effective amount of the VMAT2 inhibitor. 7. The method of claim 1, wherein the dosage and/or frequency of administration of the digoxin is reduced. 8. The method of claim 1, wherein the VMAT2 inhibitor is administered orally. 9. The method of claim 1, wherein the VMAT2 inhibitor is administered in the form of a tablet or capsule. 10. The method of claim 1, wherein the VMAT2 inhibitor is (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 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. 11. The method of claim 10, 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. 12. The method of claim 10, wherein the VMAT2 inhibitor is administered in an amount equivalent to between about 20 mg and about 160 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. 13. The method of claim 12, wherein the VMAT2 inhibitor is administered 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 once daily. 14. The method of claim 12, wherein the VMAT2 inhibitor is administered in 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. 15. The method of claim 12, wherein the VMAT2 inhibitor is administered in 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. 16. The method of claim 1, wherein the VMAT2 inhibitor is administered for a period of time in a first amount and then the amount is increased to a second amount. 17. The method of claim 16, wherein the first period of time is one week. 18. The method of claim 16, wherein the first 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-py- rido[2,1-a]isoquinolin-2-yl ester once daily. 19. The method of claim 16, wherein the second 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-py- rido[2,1-a]isoquinolin-2-yl ester once daily. 20. The method of claim 1, wherein the co-administration of the VMAT2 inhibitor with digoxin increases digoxin levels because of inhibition of intestinal P-glycoprotein (P-gp) by the VMAT2 inhibitor. 21. A method of treating tardive dyskinesia in a patient in need thereof, wherein the patient is also in need of treatment with digoxin, the method comprising: orally administering to the patient a therapeutically effective amount of a vesicular monoamine transport 2 (VMAT2) inhibitor which is (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 ditosylate, and administering the digoxin to the patient at a reduced dose to compensate for the expected increase in exposure resulting from co-administration of the digoxin and the VMAT2 inhibitor, wherein the reduced dose is relative to what the patient would be administered if the patient is not being administered the VMAT2 inhibitor. 22. The method of claim 21, wherein the therapeutically effective amount of the VMAT2 inhibitor 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. 23. The method of claim 21, wherein the therapeutically effective amount of the VMAT2 inhibitor 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. 24. The method of claim 21, wherein the therapeutically effective amount of the VMAT2 inhibitor 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. 25. The method of claim 21, wherein the co-administration of the VMAT2 inhibitor with digoxin increases digoxin levels because of inhibition of intestinal P-glycoprotein (P-gp) by the VMAT2 inhibitor.