Methods for the administration of certain VMAT2 inhibitors
Provided are methods of administering a vesicular monoamine transport 2 (VMAT2) inhibitor chosen from valbenazine and (+)-α-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 being treated with a strong cytochrome P450 3A4 (CYP3A4) inducer.
1. A method of treating a patient with a hyperkinetic movement disorder, wherein the patient is being administered a strong cytochrome P450 3A4 (CYP3A4) inducer, comprising:
discontinuing treatment of the strong CYP3A4 inducer, and then
orally administering once daily 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 a pharmaceutically acceptable salt thereof, thereby avoiding the concomitant use of the VMAT2 inhibitor with the strong CYP3A4 inducer.
2. The method of claim 1 , wherein the strong CYP3A4 inducer is chosen from nevirapine, pentobarbital, phenytoin, lumacaftor, rifabutin, rifampicin, carbamazepine, fosphenytoin, phenobarbital, primidone, enzalutamide, mitotane, and St. John's Wort.
3. The method of claim 1 , wherein the strong CYP3A4 inducer is chosen from rifampicin, carbamazepine, phenytoin, and St. John's Wort.
4. The method of claim 1 , wherein the strong CYP3A4 inducer is rifampicin.
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 hyperkinetic movement disorder is tardive dyskinesia.
7. The method of claim 1 , wherein the hyperkinetic movement disorder is chorea.
8. The method of claim 1 , wherein the hyperkinetic movement disorder is chorea associated with Huntington's disease.
9. 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.
10. 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.
11. The method of claim 1 , 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.
12. The method of claim 1 , 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 free base once daily for one week, and 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 free base once daily after one week.
13. The method of claim 1 , 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 free base once daily.
14. The method of claim 1 , 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 free base once daily.
15. The method of claim 1 , 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 free base once daily.