Formulations and pharmacokinetics of deuterated benzoquinoline inhibitors of vesicular monoamine transporter 2
The present invention relates to new pharmaceutical compositions comprising benzoquinoline compounds, and methods to inhibit vesicular monoamine transporter 2 (VMAT2) activity in a subject for the treatment of chronic hyperkinetic movement disorders.
1. An extended-release pharmaceutical formulation comprising 6 to 24 mg of d 6 -tetrabenazine and between about 5% and about 20% by weight, based on the weight of the formulation, of a poly(ethylene oxide) polymer, wherein upon administration to a subject:
the formulation provides a reduction in dose relative to a formulation comprising non-deuterated tetrabenazine; and
maintains at least the same AUC of the total combined amount of d 6 -α-dihydrotetrabenazine and d 6 -β-dihydrotetrabenazine relative to α-dihydrotetrabenazine and β-dihydrotetrabenazine of the formulation comprising non-deuterated tetrabenazine.
2. The extended-release pharmaceutical formulation of claim 1 , wherein said d 6 -tetrabenazine is (+/−)-trans-d 6 -tetrabenazine.
3. The extended-release pharmaceutical formulation of claim 1 , wherein the said reduction in dose is at least 30%.
4. The extended-release pharmaceutical formulation of claim 1 , wherein said reduction in dose is at least 40%.
5. The extended-release pharmaceutical formulation of claim 1 , wherein the formulation provides a reduction in C max of the total combined d 6 -α-dihydrotetrabenazine and d 6 -β-dihydrotetrabenazine of at least 50% relative to the C max of α-dihydrotetrabenazine and β-dihydrotetrabenazine following administration of a formulation comprising non-deuterated tetrabenazine to a subject.
6. The extended-release pharmaceutical formulation of claim 1 , wherein the C max of the total combined d 6 -α-dihydrotetrabenazine and d 6 -β-dihydrotetrabenazine is reduced by at least 50% relative to the C max of α-dihydrotetrabenazine and β-dihydrotetrabenazine achieved upon administration of an immediate-release formulation of tetrabenazine that yields at least the same AUC of the total combined α-dihydrotetrabenazine and β-dihydrotetrabenazine.
7. The extended-release pharmaceutical formulation of claim 6 , wherein the C max is reduced by at least 60%.
8. The extended-release pharmaceutical formulation of claim 6 , wherein the C max is reduced by at least 70%.
9. The extended-release pharmaceutical formulation of claim 6 , wherein the C max is reduced by at least 75%.
10. The extended-release pharmaceutical formulation of claim 1 , comprising 7.5 mg of d 6 -tetrabenazine, wherein the C max of the total combined amount of d 6 -dihydrotetrabenazine is about 21.37±6.78 ng/mL upon administration of the formulation to the subject.
11. The extended-release pharmaceutical formulation of claim 10 , wherein the AUC inf of the total combined amount of d 6 -dihydrotetrabenazine is about 176.2±69.3 hr·ng/mL mL upon administration of the formulation to the subject.
12. The extended-release pharmaceutical formulation of claim 10 , wherein the AUC (0-12) of the total combined amount of d 6 -dihydrotetrabenazine is about 110.2±32.1 hr·ng/mL upon administration of the formulation to the subject.
13. The extended-release pharmaceutical formulation of claim 10 , wherein the T max of the total combined amount of d 6 -dihydrotetrabenazine is about 3.17±0.68 hr upon administration of the formulation to the subject.
14. The extended-release pharmaceutical formulation of claim 10 , wherein the T half of the total combined amount of d 6 -dihydrotetrabenazine is about 7.18±1.35 hr upon administration of the formulation to the subject.
15. The extended-release pharmaceutical formulation of claim 1 , comprising 15 mg of d 6 -tetrabenazine, wherein the C max of the total combined amount of d 6 -dihydrotetrabenazine is about 45.33±8.31 ng/mL upon administration of the formulation to the subject.
16. The extended-release pharmaceutical formulation of claim 15 , wherein the AUC inf of the total combined amount of d 6 -dihydrotetrabenazine is about 408.3±147.2 hr·ng/mL upon administration of the formulation to the subject.
17. The extended-release pharmaceutical formulation of claim 15 , wherein the AUC (0-12) of the total combined amount of d 6 -dihydrotetrabenazine is about 250.4±64.0 hr·ng/mL upon administration of the formulation to the subject.
18. The extended-release pharmaceutical formulation of claim 15 , wherein the T max of the total combined amount of d 6 -dihydrotetrabenazine is about 3.21±0.45 hr upon administration of the formulation to the subject.
19. The extended-release pharmaceutical formulation of claim 1 , comprising 22.5 mg of d 6 -tetrabenazine, wherein the C max of the total combined amount of d 6 -dihydrotetrabenazine is about 67.49±16.72 ng/mL upon administration of the formulation to the subject.
20. The extended-release pharmaceutical formulation of claim 19 , wherein the AUC inf of the total combined amount of d 6 -dihydrotetrabenazine is about 610±291 hr·ng/mL upon administration of the formulation to the subject.
21. The extended-release pharmaceutical formulation of claim 19 , wherein the AUC (0-12) of the total combined amount of d 6 -dihydrotetrabenazine is about 370±123.7 hr·ng/mL upon administration of the formulation to the subject.
22. The extended-release pharmaceutical formulation of claim 19 , wherein the T max of the total combined amount of d 6 -dihydrotetrabenazine is about 3.79±0.84 hr upon administration of the formulation to the subject.
23. The extended-release pharmaceutical formulation of claim 1 , comprising 6 mg of d 6 -tetrabenazine, wherein the C max of the total combined amount of d 6 -dihydrotetrabenazine is about 15.5±3.5 ng/mL upon administration of the formulation to the subject with food.
24. The extended-release pharmaceutical formulation of claim 23 , wherein the AUC inf of the total combined amount of d 6 -dihydrotetrabenazine is about 132±47 hr·ng/mL upon administration of the formulation to the subject.
25. The extended-release pharmaceutical formulation of claim 23 , wherein the AUC t of the total combined amount of d 6 -dihydrotetrabenazine is about 122±46 hr·ng/mL upon administration of the formulation to the subject.
26. The extended-release pharmaceutical formulation of claim 23 , wherein the T max of the total combined amount of d 6 -dihydrotetrabenazine is about 3.74±0.99 hr upon administration of the formulation to the subject.
27. The extended-release pharmaceutical formulation of claim 1 , comprising 12 mg of d 6 -tetrabenazine, wherein the C max of the total combined amount of d 6 -dihydrotetrabenazine is about 32.1±8.1 ng/mL upon administration of the formulation to the subject with food.
28. The extended-release pharmaceutical formulation of claim 27 , wherein the AUC ia of the total combined amount of d 6 -dihydrotetrabenazine is about 289±115 hr·ng/mL upon administration of the formulation to the subject.
29. The extended-release pharmaceutical formulation of claim 27 , wherein the AUC t of the total combined amount of d 6 -dihydrotetrabenazine is about 279±114 hr·ng/mL upon administration of the formulation to the subject.
30. The extended-release pharmaceutical formulation of claim 27 , wherein the T max of the total combined amount of d 6 -dihydrotetrabenazine is about 3.90±1.27 hr upon administration of the formulation to the subject.
31. The extended-release pharmaceutical formulation of claim 1 , comprising 18 mg of d 6 -tetrabenazine, wherein the C max of the total combined amount of d 6 -dihydrotetrabenazine is about 47.8±12 ng/mL upon administration of the formulation to the subject with food.
32. The extended-release pharmaceutical formulation of claim 31 , wherein the AUC inf of the total combined amount of d 6 -dihydrotetrabenazine is about 419±165 hr*ng/mL upon administration of the formulation to the subject.
33. The extended-release pharmaceutical formulation of claim 31 , wherein the AUC t of the total combined amount of d 6 -dihydrotetrabenazine is about 407±163 hr*ng/mL upon administration of the formulation to the subject.
34. The extended-release pharmaceutical formulation of claim 31 , wherein the T max of the total combined amount of d 6 -dihydrotetrabenazine is about 3.63±0.85 hr upon administration of the formulation to the subject.
35. The extended-release pharmaceutical formulation of claim 1 , comprising 24 mg of d 6 -tetrabenazine, wherein the C max of the total combined amount of d 6 -dihydrotetrabenazine is about 60.9±13.8 ng/mL upon administration of the formulation to the subject with food.
36. The extended-release pharmaceutical formulation of claim 35 , wherein the AUC inf of the total combined amount of d 6 -dihydrotetrabenazine is about 580±229 hr*ng/mL upon administration of the formulation to the subject.
37. The extended-release pharmaceutical formulation of claim 35 , wherein the AUC t of the total combined amount of d 6 -dihydrotetrabenazine is about 569±225 hr*ng/mL upon administration of the formulation to the subject.
38. The extended-release pharmaceutical formulation of claim 35 , wherein the T max of the total combined amount of d 6 -dihydrotetrabenazine is about 3.92±1.19 hr upon administration of the formulation to the subject.
39. The extended-release pharmaceutical formulation of claim 1 , comprising between about 10% and about 20% by weight, based on the weight of the formulation, of the poly(ethylene oxide) polymer.