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 amantadine or a pharmaceutically acceptable salt of amantadine to a human patient, comprising administering said pharmaceutical composition to said human patient orally, once daily, 0-4 hours before bedtime,
wherein said pharmaceutical composition consists of: (i) 220 mg to 445 mg of amantadine or a pharmaceutically acceptable salt thereof; and (ii) or one or more excipients,
wherein at least one of said one or more excipients extends release of the amantadine or the pharmaceutically acceptable salt of amantadine to provide an extended release form,
wherein dosing said pharmaceutical composition in a single dose, fasted human pharmacokinetic study provides: a) an amantadine Tmax of 8 to 18 hours, b) an amantadine Cmax of 1.0 to 2.8 ng/ml per mg of amantadine, and c) an amantadine AUC 0-inf of 40 to 75 ng*hr/ml per mg of amantadine, and
wherein dosing the pharmaceutical composition orally, once daily, 0-4 hours before bedtime in a multiple dose, fasted human pharmacokinetic study provides a steady state plasma concentration profile for amantadine characterized by a ratio of C-ave-day to C-ave-night of 1.2 to 1.7, wherein C-ave-day is the average amantadine plasma concentration determined over the period from 9 am to 4 pm and C-ave-night is the average amantadine plasma concentration determined over a period from 11 pm to 7 am.
30 . The method of claim 29 , wherein said dosing of the pharmaceutical composition in said single dose, fasted human pharmacokinetic study provides an amantadine Tmax of 9 to 18 hours.
31 . The method of claim 29 , wherein said dosing of the pharmaceutical composition in said single dose, fasted human pharmacokinetic study provides an amantadine Tmax of 11 to 18 hours.
32 . The method of claim 29 , wherein once daily oral dosing of said pharmaceutical composition in a multiple dose, fasted human pharmacokinetic study provides a steady state amantadine plasma concentration profile characterized by an amantadine Cmax,ss of 2.4 to 4.2 ng/ml per mg of amantadine.
33 . The method of claim 29 , wherein once daily oral dosing of said pharmaceutical composition in a multiple dose, fasted human pharmacokinetic study provides a steady state amantadine plasma concentration profile characterized by an amantadine Cmin,ss of 1.1 to 2.6 ng/ml per mg of amantadine.
34 . The method of claim 29 , wherein once daily oral dosing of said pharmaceutical composition in a multiple dose, fasted human pharmacokinetic study provides a steady state amantadine plasma concentration profile characterized by an AUC 0-24 of 44 to 83 ng*hr/ml per mg of amantadine.
35 . The method of claim 29 , wherein said dosing of the pharmaceutical composition in a single dose, fasted human pharmacokinetic study provides plasma concentration profile characterized by an AUC 0-inf per mg of amantadine that is equivalent to that of a 100 mg tablet of an immediate release formulation of amantadine HCl.
36 . The method of claim 29 , wherein the pharmaceutical composition is therapeutically effective for the treatment of Parkinson's disease.
37 . The method of claim 29 , wherein the subject human patient is being treated for Parkinson's disease.
38 . The method of claim 29 , wherein the human patient suffers from dyskinesia.
39 . The method of claim 38 , wherein the dyskinesia is levodopa-induced dyskinesia.
40 . The method of claim 39 , wherein the method reduces the frequency or severity of levodopa-induced dyskinesia.
41 . The method of claim 29 , wherein the extended release form is an osmotic dosage form.
42 . The method of claim 29 , wherein the drug amantadine or pharmaceutically acceptable salt thereof is 40 to 65 wt % of the pharmaceutical composition.
43 . The method of claim 29 , wherein said steady state amantadine plasma concentration profile is characterized by a ratio of C-ave-day to C-ave-night of 1.2 to 1.6 at steady state.
44 . The method of claim 29 , wherein said steady state amantadine plasma concentration profile is characterized by a ratio of C-ave-day to C-ave-night of 1.3 to 1.7.
45 . The method of claim 29 , wherein the amantadine Tmax is the median amantadine Tmax.
46 . The method of claim 29 , wherein the amantadine Cmax is the mean amantadine Cmax.
47 . The method of claim 29 , wherein the amantadine AUC 0-inf is the mean amantadine AUC 0-inf .
48 . The method of claim 29 , wherein said human patient is suffering from Parkinson's disease, and the method additionally comprises administering to said human patient a pharmaceutically effective amount of levodopa.
49 . The method of claim 29 , wherein the pharmaceutical composition is administered as one, two, three or four unit dosage forms.
50 . The method of claim 49 , wherein said unit dosage forms comprise a capsule containing said pharmaceutical composition.