Claims for Patent: 11,903,908

Summary for Patent: 11,903,908

Title:	Methods of administering amantadine
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.
Inventor(s):	Gregory T. Went, Timothy J. Fultz, Natalie McClure
Assignee:	Adamas Pharma LLC
Application Number:	US17/088,369
Patent Claims:	1. A method of reducing OFF time in a patient with Parkinson's disease (PD), wherein the patient is being treated with a levodopa and is experiencing OFF periods, 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 of a pharmaceutically acceptable salt of amantadine, 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 300 mg to 380 mg of a pharmaceutically acceptable salt of amantadine, 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 in the patient is reduced 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 said second composition comprises 300 mg to 350 mg of a pharmaceutically acceptable salt of amantadine. 3. The method of claim 1, wherein said second composition is administered 0 to 4 hours before bedtime. 4. The method of claim 3, wherein said first composition is administered 0 to 4 hours before bedtime. 5. 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. 6. 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 AUC0-inf of 40 to 75 ng*h/mL per mg of amantadine. 7. 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 AUC0-inf after administration of a single dose. 8. The method of claim 7, wherein the second composition is characterized by a fractional AUC from 0 to 4 hours that is less than 3% of AUC0-inf after administration of a single dose. 9. 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 AUC0-inf after administration of a single dose. 10. 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) a mean Cmax of 2.2 to 4.2 ng/ml per mg of amantadine, (ii) a mean Cmin of 1.1 to 2.6 ng/ml per mg of amantadine, and (iii) a mean AUC0-24 of 46 to 73 ng*h/mL per mg of amantadine. 11. The method of claim 1, wherein ON time without troublesome dyskinesia is increased after at least 7 weeks of administering the second composition once daily to the patient, and the ratio of increased ON time without troublesome dyskinesia to decreased OFF time is 4.1:1.0 to 3.8:0.6. 12. The method of claim 1, wherein the reduction of OFF time is determined in a placebo controlled, double blind clinical study. 13. The method of claim 12, wherein the total daily amount of OFF time is reduced by 10% to 40% relative to placebo, as determined using a PD Home Diary. 14. The method of claim 12, wherein the subjects administered placebo in the placebo controlled, double blind clinical study were administered placebo for at least 8 weeks. 15. The method of claim 1, wherein said first composition comprises 170 mg of a pharmaceutically acceptable salt of amantadine. 16. The method of claim 15, wherein said first composition comprises 170 mg of amantadine hydrochloride. 17. The method of claim 16, wherein said second composition comprises 300 mg to 350 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 15, wherein said second composition comprises 340 mg of a pharmaceutically acceptable salt of amantadine. 20. The method of claim 1, wherein said second composition comprises 300 mg to 350 mg of amantadine hydrochloride. 21. The method of claim 1, wherein said second composition comprises 340 mg of amantadine hydrochloride. 22. The method of claim 1, wherein said second composition comprises 2 unit dosage forms. 23. The method of claim 17, wherein said second composition comprises 2 unit dosage forms. 24. The method of claim 1, wherein said first composition comprises 2 unit dosage forms. 25. The method of claim 17, wherein said first composition comprises 2 unit dosage forms. 26. 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 Tmax of 9 to 18 hours. 27. The method of claim 26, wherein the average Tmax is 12 to 18 hours. 28. 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. 29. The method of claim 6, wherein the average Cmax is 1.1 to 1.7 ng/ml per mg of amantadine. 30. The method of claim 6, wherein the average Cmax is 1.6 to 2.4 ng/ml per mg of amantadine. 31. The method of claim 6, wherein the average Cmax is 1.7 to 2.4 ng/ml per mg of amantadine. 32. The method of claim 6, wherein the average AUC0-inf is 46 to 56 ng*h/mL per mg of amantadine. 33. The method of claim 6, wherein the average AUC0-inf is 46 to 75 ng*h/mL per mg of amantadine. 34. The method of claim 6, wherein the average AUC0-inf is 40 to 56 ng*h/mL per mg of amantadine. 35. The method of claim 10, wherein the mean Cmax is 2.2 to 2.7 ng/ml per mg of amantadine. 36. The method of claim 10, wherein the mean Cmax is 2.4 to 4.2 ng/ml per mg of amantadine. 37. The method of claim 10, wherein the mean Cmax is 2.4 to 2.7 ng/ml per mg of amantadine. 38. The method of claim 10, wherein the mean Cmin is 1.4 to 1.7 ng/ml per mg of amantadine. 39. The method of claim 10, wherein the mean Cmin is 1.4 to 2.6 ng/ml per mg of amantadine. 40. The method of claim 10, wherein the mean Cmin is 1.1 to 1.7 ng/ml per mg of amantadine. 41. The method of claim 10, wherein the mean AUC0-24 is 46 to 56 ng*h/mL per mg of amantadine. 42. The method of claim 10, wherein the mean AUC0-24 is 48 to 73 ng*h/mL per mg of amantadine. 43. The method of claim 10, wherein the mean AUC0-24 is 48 to 56 ng*h/mL per mg of amantadine. 44. A method of reducing OFF time in a patient with Parkinson's disease (PD), wherein the patient is being treated with levodopa and is experiencing OFF periods, 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 in the patient is reduced after at least 7 weeks of administering the second composition once daily to the patient; wherein the plasma concentration of amantadine in the patient is increased less than 10% at 1 hour after administration of the first or second composition; and wherein the reduction of OFF time is determined in a placebo controlled, double blind clinical study. 45. The method of claim 44, 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. 46. The method of claim 44, wherein the second composition is characterized by a fractional AUC from 0 to 4 hours that is less than 5% of AUC0-inf after administration of a single dose.