Methods for the administration of certain VMAT2 inhibitors

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-pyrido[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-pyrido[2,1-a]isoquinolin-2-yl ester and its active metabolite, (+)-α-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 max or AUC 0-∞.

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-pyrido[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, (+)-α-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 max .

21. The method of claim 20 , wherein the exposure is measured by AUC 0-∞.

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-pyrido[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-pyrido[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.