Methods of administering amantadine

• US 10,646,456 B2
• Filed: 11/13/2018
• Issued: 05/12/2020
• Est. Priority Date: 06/17/2013
• Status: Active Grant

• Current Assignee: Adamas Pharma, LLC (Supernus Pharmaceuticals, Inc.)
• Original Assignee: Adamas Pharma, LLC (Supernus Pharmaceuticals Incorporated)
• Inventors: Went, Gregory T., Fultz, Timothy J., McClure, Natalie
• Primary Examiner(s): Pihonak, Sarah
• Application Number:
  US16/188,770
• Publication Number:
  US 20190307707A1
• Time in Patent Office: 546 Days
• CPC Class Codes: A61K 31/13 Amines A61K31/04 takes precedence
• CPC Class Codes: A61K 9/1652 Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin homeopathic globules A61K9/1623
• CPC Class Codes: A61K 9/5026 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/5047 Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/5078 with drug-free core

Abstract

Methods of nighttime administration of amantadine to reduce sleep disturbances in patient undergoing treatment with amantadine are described, as well as compositions of extended release amantadine that are suitable for nighttime administration.

Claims

1. A method of reducing OFF time and increasing ON time without troublesome dyskinesia in a patient with Parkinson'"'"'s disease (PD), wherein the patient is being treated with levodopa, the method comprising:

(1) orally administering to said patient once daily for at least one week a first composition comprising 85 mg to 170 mg amantadine, or a pharmaceutically acceptable salt thereof, and at least one excipient that modifies the release of at least a portion of the amantadine or pharmaceutically acceptable salt thereof to provide an extended release form; and

thereafter

(2) orally administering to said patient once daily a second composition comprising about 260 mg to 380 mg amantadine, or a pharmaceutically acceptable salt thereof, and at least one excipient that modifies the release of at least a portion of the amantadine or pharmaceutically acceptable salt thereof to provide an extended release form;

wherein OFF time is reduced and ON time without troublesome dyskinesia is increased after at least 7 weeks of administering the second composition once daily to the patient; and

wherein the plasma concentration of amantadine in the patient is increased less than 10% at 1 hour after administration of the second composition.

2. The method of claim 1, wherein the reduction of OFF time and increase of ON time without troublesome dyskinesia is determined in a placebo controlled, double blind clinical study.

3. The method of claim 1, wherein the total daily amount of OFF time in the patient with Parkinson'"'"'s disease is reduced 10% to 40% as determined using a PD Home Diary, relative to before administering the first composition.

4. The method of claim 1, wherein the total daily amount of ON time without troublesome dyskinesia is increased by at least double the amount that the OFF time is decreased.

5. The method of claim 1, wherein the total daily amount of ON time with dyskinesia is not increased.

6. The method of claim 1, wherein the total daily amount of ON time with troublesome dyskinesia is not increased.

7. The method of claim 4, wherein the total daily amount of OFF time in the patient with Parkinson'"'"'s disease is reduced 10% to 40% as determined using a PD Home Diary, relative to before administering the first composition.

8. The method of claim 2, wherein the total daily amount of OFF time is reduced by 10% to 40% relative to placebo, as determined using a PD Home Diary.

9. The method of claim 1, wherein the total daily amount of ON time without troublesome dyskinesia is increased by 38% to 48% relative to placebo, as determined using a PD Home Diary.

10. The method of claim 1, wherein said second composition is administered 0 to 4 hours before bedtime.

11. The method of claim 1, wherein when said second composition is dosed in a single dose, fasted, human pharmacokinetic study, a C-ave-day is determined from 9 am to 4 pm, and a C-ave-night is determined from 11 pm to 7 am, the C-ave-day is 1.4 to 1.7 times the C-ave-night.

12. The method of claim 1, wherein administration of a single dose of said second composition to a cohort of human healthy volunteer subjects in a fasted state provides an average Cmax of 1.1 to 2.4 ng/ml per mg of amantadine or an AUC_0-inf of 40 to 75 ng*h/mL per mg of amantadine.

13. The method of claim 1, wherein the once daily oral administration of a dose of said second composition to a cohort of human volunteers provides a steady state plasma concentration profile characterized by at least one of:

(i) an average Cmax of 2.2 to 4.2 ng/ml per mg of amantadine, (ii) an average Cmin of 1.1 to 2.6 ng/ml per mg of amantadine, and (iii) an average AUC_0-24 of 46 to 73 ng*h/mL per mg of amantadine.

14. The method of claim 1, wherein said second composition comprises 260 mg to 305 mg amantadine.

15. The method of claim 1, wherein said second composition comprises 270 mg to 285 mg amantadine.

16. The method of claim 1, wherein said second composition comprises 300 mg to 380 mg of a pharmaceutically acceptable salt of amantadine.

17. The method of claim 16, wherein said second composition comprises 300 mg to 380 mg of amantadine hydrochloride.

18. The method of claim 17, wherein said second composition comprises 340 mg of amantadine hydrochloride.

19. The method of claim 1, wherein said first composition comprises 85 mg to 170 mg of a pharmaceutically acceptable salt of amantadine.

20. The method of claim 19, wherein said first composition comprises 170 mg of a pharmaceutically acceptable salt of amantadine.

21. The method of claim 20, wherein said first composition comprises 170 mg of amantadine hydrochloride.

22. The method of claim 17, wherein said first composition comprises 170 mg of amantadine hydrochloride.

23. The method of claim 16, wherein said first composition comprises 85 mg to 170 mg of a pharmaceutically acceptable salt of amantadine.

24. The method of claim 23, wherein said first composition comprises 170 mg of a pharmaceutically acceptable salt of amantadine.

25. The method of claim 20, wherein said second composition comprises 340 mg of a pharmaceutically acceptable salt of amantadine.

26. The method of claim 1, wherein said second composition comprises 2 unit dosage forms.

27. The method of claim 22, wherein said second composition comprises 2 unit dosage forms.

28. The method of claim 1, wherein said first composition comprises 2 unit dosage forms.

29. The method of claim 1, wherein administration of a single dose of said second composition to a cohort of human healthy volunteer subjects in a fasted state provides an average T_max of 9 to 18 hours.

30. The method of claim 29, wherein the average T_max is 12 to 18 hours.

31. The method of claim 12, wherein the average Cmax is 1.1 to 1.7 ng/ml per mg of amantadine.

32. The method of claim 12, wherein the average Cmax is 1.6 to 2.4 ng/ml per mg of amantadine.

33. The method of claim 12, wherein the average Cmax is 1.7 to 2.4 ng/ml per mg of amantadine.

34. The method of claim 12, wherein the average AUC_0-inf is 46 to 56 ng*h/mL per mg of amantadine.

35. The method of claim 12, wherein the average AUC_0-inf is 46 to 75 ng*h/mL per mg of amantadine.

36. The method of claim 12, wherein the average AUC_0-inf is 40 to 56 ng*h/mL per mg of amantadine.

37. The method of claim 13, wherein the average Cmax is 2.2 to 2.7 ng/ml per mg of amantadine.

38. The method of claim 13, wherein the average Cmax is 2.4 to 4.2 ng/ml per mg of amantadine.

39. The method of claim 13, wherein the average Cmax is 2.4 to 2.7 ng/ml per mg of amantadine.

40. The method of claim 13, wherein the average Cmin is 1.4 to 1.7 ng/ml per mg of amantadine.

41. The method of claim 13, wherein the average Cmin is 1.4 to 2.6 ng/ml per mg of amantadine.

42. The method of claim 13, wherein the average Cmin is 1.1 to 1.7 ng/ml per mg of amantadine.

43. The method of claim 13, wherein the average AUC_0-24 is 46 to 56 ng*h/mL per mg of amantadine.

44. The method of claim 13, wherein the average AUC_0-24 is 48 to 73 ng*h/mL per mg of amantadine.

45. The method of claim 13, wherein the average AUC_0-24 is 48 to 56 ng*h/mL per mg of amantadine.

46. The method of claim 2, wherein the subjects administered placebo in the placebo controlled, double blind clinical study were administered placebo for at least 8 weeks.

47. The method of claim 1, wherein the second composition is characterized by a fractional AUC from 0 to 8 hours that is about 5 to 15% of AUC_0-inf after administration of a single dose.

48. The method of claim 1, wherein the second composition is characterized by a fractional AUC from 0 to 4 hours that is less than 5% of AUC_0-inf after administration of a single dose.

49. The method of claim 48, wherein the second composition is characterized by a fractional AUC from 0 to 4 hours that is less than 3% of AUC_0-inf after administration of a single dose.

56. The method of claim 1, wherein the first and second compositions are formulated as one or two capsules comprising amantadine, or a pharmaceutically acceptable salt thereof, and at least one excipient that modifies the release of at least a portion of the amantadine or pharmaceutically acceptable salt thereof to provide an extended release form.

57. The method of claim 56, wherein the first composition comprises one of the capsules and the second composition comprises two of the capsules.

58. The method of claim 57, wherein each capsule comprises the same formulation.

50. A method of reducing OFF time and increasing ON time without troublesome dyskinesia in a patient with Parkinson'"'"'s disease (PD), wherein the patient is being treated with levodopa, the method comprising:

(1) orally administering to said patient once daily for at least one week a first composition comprising 260 mg amantadine hydrochloride and at least one excipient that modifies the release of at least a portion of the amantadine hydrochloride to provide an extended release form; and

thereafter

(2) orally administering to said patient once daily a second composition comprising 290 mg to 325 mg amantadine hydrochloride and at least one excipient that modifies the release of at least a portion of the amantadine hydrochloride to provide an extended release form;

wherein OFF time is reduced and ON time without troublesome dyskinesia is increased after at least 7 weeks of administering the second composition once daily to the patient; and

wherein the plasma concentration of amantadine in the patient is increased less than 10% at 1 hour after administration of second composition.

51. The method of claim 50, wherein the total daily amount of OFF time in the patient with Parkinson'"'"'s disease is reduced 10% to 40% as determined using a PD Home Diary, relative to before administering the first composition.

52. The method of claim 50, wherein the total daily amount of ON time without troublesome dyskinesia is increased between 3.8 and 4.1 hours, as determined using a PD Home Diary, relative to before administering the first composition.

53. The method of claim 50, wherein the total daily amount of ON time with dyskinesia is not increased.

54. The method of claim 50, wherein the total daily amount of ON time with troublesome dyskinesia is not increased.

55. The method of claim 50, wherein the second composition is characterized by a fractional AUC from 0 to 4 hours that is less than 5% of AUC_0-inf after administration of a single dose.