AMANTADINE COMPOSITIONS AND METHODS OF USE
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.
1 - 28 . (canceled)
29 . A method of administering a pharmaceutical composition of a drug selected from the group consisting of amantadine and pharmaceutically acceptable salts thereof, comprising administering the pharmaceutical composition of the drug to a human subject orally, once daily at a time such that the drug does not interfere with sleep,
wherein said pharmaceutical composition consists of (i) 220 mg to 445 mg of said drug and (ii) at least one excipient,
wherein at least one of said excipients modifies the release of the drug to provide an extended release form,
wherein administration of the pharmaceutical composition provides a) a Tmax of 5 to 18 hours, b) a Cmax of 1.0 to 2.8 ng/ml per mg amantadine, and c) an AUC 0-inf of 40 to 75 ng*hr/ml per mg amantadine as determined from a single dose, fasted, human pharmacokinetic study, and
wherein administration of the pharmaceutical composition once daily provides a ratio of C-ave-day/C-ave-night of 1.2 to 1.7 at steady state as determined from a fasted human pharmacokinetic study, wherein C-ave-day is determined over the period from 9 am to 4 pm and C-ave-night is determined over the period from 11 pm to 7 am.
30 . A method of reducing sleep disturbances in a patient undergoing amantadine therapy, comprising orally administering a pharmaceutical composition of a drug selected from the group consisting of amantadine and pharmaceutically acceptable salts thereof to said patient once daily,
wherein said pharmaceutical composition consists of (i) 220 mg to 445 mg of said drug and (ii) at least one excipient,
wherein at least one of said excipients modifies the release of the drug to provide an extended release form,
wherein administration of the pharmaceutical composition provides a) a Tmax of 5 to 18 hours, b) a Cmax of 1.0 to 2.8 ng/ml per mg amantadine, and c) an AUC 0-inf of 40 to 75 ng*hr/m1 per mg amantadine as determined from a single dose, fasted, human pharmacokinetic study, and
wherein administration of the pharmaceutical composition once daily provides a ratio of C-ave-day/C-ave-night of 1.2 to 1.7 at steady state as determined from a fasted human pharmacokinetic study, wherein C-ave-day is determined over the period from 9 am to 4 pm and C-ave-night is determined over the period from 11 pm to 7 am.
31 . The method of claim 29 or claim 30 , wherein administration of the pharmaceutical composition provides a Tmax of 6 to 9 hours as determined from a single dose, fasted, human pharmacokinetic study.
32 . The method of claim 29 or claim 30 , wherein administration of the pharmaceutical composition provides a Tmax of 8 to 18 hours as determined from a single dose, fasted, human pharmacokinetic study.
33 . The method of claim 29 or claim 30 , wherein the administration of the pharmaceutical composition is 0 to 4 hours before bedtime.
34 . The method of claim 29 or claim 30 , wherein once daily administration of the pharmaceutical composition provides a steady state plasma concentration profile characterized by a Cmax of 2.4 to 4.2 ng/ml per mg of amantadine as determined from a fasted human pharmacokinetic study.
35 . The method of claim 34 , wherein once daily administration of the pharmaceutical composition provides a steady state plasma concentration profile characterized by a Cmin of 1.1 to 2.6 ng/ml per mg of amantadine as determined from a fasted human pharmacokinetic study.
36 . The method of claim 29 or claim 30 , wherein once daily administration of the pharmaceutical composition provides a steady state plasma concentration profile characterized by a Cmin of 1.1 to 2.6 ng/ml per mg of amantadine as determined from a fasted human pharmacokinetic study.
37 . The method of claim 29 or claim 30 , wherein once daily administration of the pharmaceutical composition provides a steady state plasma concentration profile characterized by an AUC 0-24 of 44 to 83 ng*hr/ml per mg of amantadine as determined from a fasted human pharmacokinetic study.
38 . The method of claim 29 or claim 30 , wherein at least some of the drug is in an immediate release form.
39 . The method of claim 29 or claim 30 , wherein at least 50% of the drug is in the extended release form.
40 . The method of claim 29 or claim 30 , wherein at least 75% of the drug is in the extended release form.
41 . The method of claim 29 or claim 30 , wherein at least 90% of the drug is in the extended release form.
42 . The method of claim 29 or claim 30 , wherein the pharmaceutical composition provides a single dose AUC 0-inf per mg amantadine that is equivalent to that of a 100 mg tablet of an immediate release formulation of amantadine HCl.
43 . The method of claim 29 or claim 30 , wherein once daily administration of the pharmaceutical composition maximizes daytime plasma exposure to amantadine while minimizing night plasma exposure at steady state.
44 . The method of claim 29 or claim 30 , wherein the pharmaceutical composition is therapeutically effective for the treatment of Parkinson's disease.
45 . The method of claim 29 , wherein the human subject is being treated for Parkinson's disease.
46 . The method of claim 30 , wherein the patient is being treated for Parkinson's disease.
47 . The method of claim 29 , wherein the human subject suffers from dyskinesia.
48 . The method of claim 30 , wherein the patient suffers from dyskinesia.
49 . The method of claim 47 or claim 48 , wherein the dyskinesia is levodopa-induced dyskinesia.
50 . The method of claim 47 or claim 48 , wherein the method reduces the frequency or severity of dyskinesia.
51 . The method of claim 29 or claim 30 , wherein the extended release form is an osmotic dosage form.
52 . The method of claim 29 or claim 30 , wherein the drug is 40 to 65 wt % of the pharmaceutical composition.
53 . The method of claim 29 or claim 30 , wherein administration of the pharmaceutical composition once daily provides a ratio of C-ave-day/C-ave-night of 1.2 to 1.6 at steady state as determined from a fasted human pharmacokinetic study.
54 . The method of claim 29 or claim 30 , wherein the administration of said pharmaceutical composition once daily provides a ratio of C-ave-day/C-ave-night of 1.3 to 1.7 at steady state as determined from a fasted human pharmacokinetic study.
55 . The method of claim 29 or claim 30 , wherein the Tmax is the median Tmax.
56 . The method of claim 29 or claim 30 , wherein the Cmax is the mean Cmax.
57 . The method of claim 29 or claim 30 , wherein the AUC 0-inf is the mean AUC 0-inf .
58 . The method of claim 29 , wherein the subject is suffering from Parkinson's disease, and the method additionally comprises administering to the subject a pharmaceutically effective amount of levodopa.
59 . The method of claim 30 , wherein the patient is suffering from Parkinson's disease, and the method additionally comprises administering to the patient a pharmaceutically effective amount of levodopa.
60 . The method of claim 29 or 30 , wherein the pharmaceutical composition is administered as one, two, three or four unit dosage forms.
61 . The method of claim 32 , wherein the administration of the pharmaceutical composition is 0 to 4 hours before bedtime.