Composition and method for treating neurological disease
Inventors
Meyer, Glenn A. • Faour, Joaquina • Pastini, Ana Cristina • Befumo, Marcelo Fernando
Assignees
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Publication Number
US-10512617-B2
Publication Date
2019-12-24
Expiration Date
Abstract
The present disclosure is directed to methods of treating neurological disorders in a patient such as Parkinson's disease, drug-induced extrapyramidal reactions, and/or levodopa-induced dyskinesia comprising administering to the patient once daily in the morning a pharmaceutical composition comprising about 50 mg to about 400 mg of extended-release amantadine or a pharmaceutically acceptable salt thereof.
Core Innovation
The invention relates to a method of treating Parkinson’s disease in a patient using once daily in the morning administration of a solid oral dosage form of a pharmaceutical composition containing amantadine free base equivalent. The pharmaceutical composition includes an extended release component comprising amantadine free base equivalent and an immediate release component comprising about 48 mg of amantadine free base equivalent. A dose-escalation regimen is provided in which the dose is initially about 129 mg for about one week and is then increased to about 193 mg once daily in the morning, with a maximum daily dose of about 322 mg of amantadine free base equivalent.
The pharmaceutical composition is characterized by pharmacokinetic performance constraints after a single-dose administration. For the composition comprising about 129 mg, the mean Cmax is defined relative to the same quantity of amantadine (or a pharmaceutically acceptable salt thereof) in an immediate release form, and in some dependent limitations is also defined by an absolute mean Cmax range. For the composition comprising about 193 mg, the mean Cmax is defined relative to the same quantity in an immediate release form, with corresponding dependent limitations including an absolute mean Cmax range. In further embodiments, the method specifies mean AUC0-∞ ranges after single-dose administration, also expressed relative to immediate release and with certain absolute numeric ranges.
In addition to the Parkinson’s disease treatment regimen, the document describes extended-release amantadine administered once daily in the morning to treat neurological disorders including drug-induced extrapyramidal reactions and levodopa-induced dyskinesia. Reported clinical efficacy indicators include reductions in levodopa-induced dyskinesia using UDysRS and increased awake ON hours without troublesome dyskinesia, alongside safety observations. The document further describes additional Phase 3 trials for drug-induced extrapyramidal reactions using rating scales.
Claims Coverage
The partial content provides four independent claims directed to treating Parkinson’s disease using once-daily morning solid oral amantadine extended-release/immediate-release regimens. Across the independent claims, inventive features are anchored in a defined dose-escalation scheme, a specific ER+IR composition structure with a fixed IR amount, maximum daily dose, and pharmacokinetic exposure targets expressed as mean Cmax and/or mean AUC0-∞ relative to immediate-release comparators.
Once-daily morning solid oral ER/IR amantadine dose escalation
Administer once daily in the morning a solid oral dosage form comprising an extended release component comprising amantadine free base equivalent and an immediate release component comprising about 48 mg amantadine free base equivalent, beginning with about 129 mg amantadine free base equivalent for about one week and then increasing to about 193 mg amantadine free base equivalent, with a maximum daily dose of about 322 mg of amantadine free base equivalent.
Cmax exposure window versus immediate release
Define pharmacokinetics after a single-dose administration such that the mean Cmax of the pharmaceutical composition comprising about 129 mg amantadine free base equivalent is between about 50% and about 125% of the mean Cmax provided by the same quantity of amantadine (or a pharmaceutically acceptable salt thereof) in an immediate release form, and the mean Cmax of the pharmaceutical composition comprising about 193 mg amantadine free base equivalent is between about 50% and about 175% of the mean Cmax provided by the same quantity in an immediate release form.
AUC0-∞ exposure window versus immediate release
Define pharmacokinetics after a single-dose administration such that the mean AUC0-∞ of the pharmaceutical composition comprising about 129 mg amantadine free base equivalent is between 65% and about 135% of the mean AUC0-∞ provided by the same quantity of amantadine (or a pharmaceutically acceptable salt thereof) in an immediate release form, and the mean AUC0-∞ of the pharmaceutical composition comprising about 193 mg amantadine free base equivalent is between 85% and about 225% of the mean AUC0-∞ provided by the same quantity in an immediate release form.
Additional dose step with higher Cmax window
Administer once daily in the morning a solid oral dosage form as an ER/IR amantadine composition with an initial about 129 mg dose for about one week, then increase to about 193 mg of amantadine free base equivalent for at least one week, and then increase to about 258 mg of amantadine free base equivalent, with a maximum daily dose of about 322 mg of amantadine free base equivalent, while defining the mean Cmax windows versus immediate release for about 129 mg, about 193 mg, and about 258 mg doses.
Across the independent claims, the core coverage is a Parkinson’s disease treatment regimen using once-daily morning solid oral amantadine compositions that combine an extended release component with a fixed immediate release component amount (about 48 mg), together with dose-escalation steps (about 129 mg to about 193 mg, and in one embodiment to about 258 mg), maximum daily dose (about 322 mg), and pharmacokinetic constraints using mean Cmax and/or mean AUC0-∞ expressed relative to immediate release.
Stated Advantages
Reductions in levodopa-induced dyskinesia as measured using UDysRS.
Increased awake ON hours without troublesome dyskinesia.
No dose dumping is described in connection with in vitro dissolution profiles.
Documented Applications
Treating Parkinson’s disease in a patient using once daily in the morning administration of an extended-release amantadine regimen.
Treating drug-induced extrapyramidal reactions using extended-release amantadine, including additional Phase 3 trials and rating scales.
Treating levodopa-induced dyskinesia using extended-release amantadine, with reported UDysRS indicators and awake ON hours without troublesome dyskinesia.
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