Extended-release Amantadine Research Articles

Extended-release amantadine for OFF-related dystonia in Parkinson's disease

IntroductionDystonia is a painful OFF-related complication in Parkinson's disease (PD) with limited treatment options. MethodsPost-hoc analysis using pooled data from two extended-release amantadine pivotal trials and follow-on open-label extension. Dystonia was assessed using the Unified Dyskinesia Rating Scale (UDysRS) Part 2 and the Movement Disorder Society-Unified PD Rating Scale (MDS-UPDRS) item 4.6. ResultsOf 196 participants, 119 (60.7%) reported OFF-related dystonia at baseline per UDysRS. Twelve-week treatment with extended-release amantadine improved OFF dystonia (treatment differences vs placebo: UDysRS Part 2, -1.0 [-1.9,-0.1]; p = 0.03 and MDS-UPDRS Item 4.6, −0.3 [-0.6,-0.05]; p = 0.02). There was no correlation between changes in OFF time and changes in OFF dystonia. Double-blind improvements in OFF dystonia were sustained throughout the 2-year follow-up. ConclusionsExtended-release amantadine yielded a sustained reduction in OFF-related dystonia in PD patients that was independent from a reduction in OFF time. A randomized controlled trial is warranted to confirm these findings.

Importance of time to ON versus wearing OFF in total daily OFF time experienced by patients with Parkinson's disease

Most patients with Parkinson's disease (PD) receiving levodopa (LD)/DOPA decarboxylase inhibitors develop motor fluctuations with an increasing amount of OFF time, negatively impacting patient quality of life. Herein, we review the evidence supporting the substantial, yet underappreciated contribution of delays in time to ON (including delayed ON and no ON) to total daily OFF time. Most clinical studies use patient diaries that do not capture time to ON and wearing OFF separately as related to LD dosing, and consequently, most OFF time has generally been attributed to wearing OFF. Hence, most treatment regimens focus on reducing wearing OFF by changing LD dosing/formulations and/or using “ON-extenders” (eg, catechol-o-methyltransferase inhibitors, monoamine oxidase-B inhibitors, extended-release amantadine, and adenosine A2A receptor antagonists). However, the literature describing approved treatments for PD that has focused on delays in time to ON is sparse and suggests this type of OFF may comprise more than twice the amount of total daily OFF time as wearing OFF. Here, we advocate for the importance of measuring and adequately addressing delays in time to ON and build support for the consistent inclusion of the time to ON measurement in future clinical trials.

Aminoadamantanes: from treatment of Parkinson’s and Alzheimer’s disease to symptom amelioration of long COVID-19 syndrome?

ABSTRACT Introduction The aminoadamantanes amantadine and memantine are well known. They mainly act as N-methyl-D-aspartate antagonists. Areas covered The antiviral drug amantadine moderately ameliorates impaired motor behavior in patients with Parkinson’s disease. Memantine provides beneficial effects on memory function in patients with advanced Alzheimer’s disease already treated with acetylcholine esterase inhibitors. Both compounds counteract impaired monoamine neurotransmission with associated symptoms, such as depression. They improve vigilance, lack of attention and concentration, fatigue syndromes according to clinical findings in patients with chronic neurodegenerative processes. Their extrasynaptic N-methyl-D-Aspartate receptor blockade weakens a prolonged influx of Ca2+ ions as the main responsible components of neuronal excitotoxicity. This causes neuronal dying and associated functional deficits. Expert opinion We suggest aminoadamantanes as future therapies for amelioration of short- and long-term consequences of a COVID 19 infection. Particularly the extended-release amantadine formulations will be suitable. They showed better clinical efficacy compared with the conventional available compounds. Amantadine may particularly be suitable for amelioration of fatigue or chronic exhaustion, memantine for improvement of cognitive deficits. Clinical research in patients, who are affected by the short- and long-term consequences of a COVID 19 infection, is warranted to confirm these still hypothetical putative beneficial effects of aminoadamantanes.

Amantadine extended release capsules (GOCOVRI®) in Parkinson’s disease: a profile of its use in the USA

Amantadine extended release (ER) [GOCOVRI®], an NMDA receptor antagonist, is an important treatment option in the management of levodopa-induced dyskinesia (LID) and OFF episodes in patients with Parkinson’s disease (PD). Taken at bedtime, amantadine ER provides low plasma levels overnight and high plasma concentrations during the waking day (i.e. delayed release). In randomized, double-blind, placebo-controlled phase III trials in adults with PD, once-daily amantadine ER was effective in improving LID, reducing OFF time and increasing ON time without troublesome dyskinesia, compared with placebo. Control of motor complications with amantadine ER was evident throughout the day, with fewer transitions between motor states. The clinical benefits of amantadine ER in reducing the duration and impact of dyskinesia and OFF episodes were durable with long-term treatment. Amantadine ER is generally well tolerated, including in the long term, with the majority of adverse events being mild or moderate in severity.

Development, Efficacy and Safety of Once-daily, Bedtime, Extended-release Amantadine (Gocovri®) to Treat Dyskinesia and OFF Time in Parkinson’s Disease

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Bioavailability and Pharmacokinetics of Once-Daily Amantadine Extended-Release Tablets in Healthy Volunteers: Results from Three Randomized, Crossover, Open-Label, Phase 1 Studies.

IntroductionIn February 2018, OS320—an amantadine extended-release (ER) tablet formulation with once-daily morning administration—was approved for the treatment of Parkinson’s disease and drug-induced extrapyramidal reactions in adults. The purpose of this study was to describe three phase 1 studies that assessed the pharmacokinetics (PK) and bioavailability of amantadine ER in healthy adult volunteers.MethodsStudy 1 was an open-label, four-treatment, single-dose, crossover study comparing amantadine ER 129, 193, and 258 mg tablets with an equivalent dose of immediate-release (IR) amantadine 40 mg/5 mL syrup. Study 2 was an open-label, single-dose, crossover food-effect study with amantadine ER 258 mg. Study 3 was an open-label, multiple-dose, crossover study comparing amantadine ER and amantadine IR syrup.ResultsAmantadine ER displayed a steady release of amantadine, with the peak amantadine concentration occurring at ~ 7.5 h postdose or in the middle of the day (following a morning dose) with steady-state administration. Administration of amantadine ER 258 mg with a high-fat meal did not affect amantadine bioavailability. Amantadine plasma exposure increased proportionally with increasing doses, and at steady state, amantadine exposure from an amantadine ER 258-mg tablet was bioequivalent to twice-daily 129-mg amantadine IR syrup.ConclusionThe PK profile of amantadine ER 129-mg, 193-mg, and 258-mg tablets allows for once-daily dosing in the morning; the 24-h average amantadine plasma concentration is equivalent to that for the same daily dose of IR amantadine administered twice daily.FundingOsmotica Pharmaceutical US LLC.

Efficacy and safety of extended-release amantadine in levodopa-induced dyskinesias: a meta-analysis.

Aim: To determine the effectiveness and safety of extended-release amantadine (ADS-5102) for levodopa-induced dyskinesias (LID) in patients with Parkinson disease (PD) by conducting a meta-analysis of relevant trials. Methods: The electronic databases were searched on or before March 1, 2019 for relevant trials. Only randomized, double-blind, parallel-group, placebo-controlled trials using ADS-5102 for LID in PD were included. Results: The ADS-5102 showed a reduction in the dyskinesia scores (mean difference: -9.56:CI: -10.05 to -9.07; p<0.00001) and in the on time without troublesome dyskinesia (mean difference 2.50:CI 2.38 to 2.63; p<0.00001). The adverse events identified in ADS-5102 were visual hallucinations, constipation, dry mouth and fall. Conclusion: ADS-5102 can be used as an adjunct therapy for LID.

Effects of Renal Impairment on the Pharmacokinetics of Once-Daily Amantadine Extended-Release Tablets.

BackgroundAn extended-release formulation of amantadine (Osmolex ER™, Osmotica Pharmaceutical US LLC) was approved in February 2018 to treat Parkinson’s disease and drug-induced extrapyramidal reactions in adults.ObjectivesTo determine the pharmacokinetic profile of extended-release amantadine in subjects with varying degrees of renal impairment.MethodsAdults with normal renal function (creatinine clearance > 89 mL/min/1.73 m2), moderate renal impairment (creatinine clearance 30–59 mL/min/1.73 m2), or severe renal impairment (estimated glomerular filtration rate < 30 mL/min/1.73 m2) received a single 129-mg dose (160 mg amantadine hydrochloride) of extended-release amantadine. Blood and urine samples for pharmacokinetic analysis were taken at scheduled intervals. A two-compartment pharmacokinetic population model was employed to determine optimum extended-release amantadine dosing in subjects with renal impairment.ResultsFollowing a single oral dose of the 129-mg extended-release amantadine tablet, amantadine plasma concentration increased slowly, reaching a peak at approximately 11 h. Amantadine elimination was reduced in subjects with renal impairment. Renal clearance decreased from 10,965 to 2618 mL/h in subjects with severe renal impairment compared to those with normal renal function. Pharmacokinetic modeling and simulation methods were used to recommend the oral administration of 129-mg extended-release amantadine tablets at intervals of 24, 48, 72, 96, 120, or 168 h depending on the degree of renal function.ConclusionsRenal impairment was associated with reduced amantadine clearance. Based on pharmacokinetic modeling and simulations, dose regimens were recommended for subjects with impaired renal function to provide systemic amantadine exposure similar to subjects with normal renal function taking a once-daily extended-release amantadine tablet.Electronic supplementary materialThe online version of this article (10.1007/s40263-019-00651-1) contains supplementary material, which is available to authorized users.

Recent Clinical Advances in Pharmacotherapy for Levodopa-Induced Dyskinesia.

Onset of involuntary movement patterns of the face, body and limbs are known as dyskinesia. They mostly appear in association with long-term levodopa (L-dopa) therapy in patients with Parkinson's disease. Consequences include patient distress, caregiver embarrassment and reduced quality of life. A severe intensity of this motor complication may result in troublesome disability; however, patients typically prefer motor behaviour with slight, non-troublesome dyskinesia to 'OFF' states. Pharmacotherapy of dyskinesia is complex. Continuous nigrostriatal postsynaptic dopaminergic receptor stimulation may delay onset of L-dopa-associated dyskinesia, while non-physiological, 'pulsatile' receptor stimulation facilitates appearance of dyskinesia. In the past, there have been many clinical trial failures with compounds that were effective in animal models of dyskinesia. Only the N-methyl-D-aspartate antagonist amantadine has shown moderate antidyskinetic effects in small well-designed clinical studies. Amantadine is an old antiviral compound, which moderately improves impaired motor behaviour. Recently, there has been a resurgence of its use due to the US Food and Drug Administration approval of an extended-release (ER) amantadine formulation for treatment of L-dopa-induced dyskinesia. This pharmacokinetic innovation improved dyskinesia and 'OFF' states in pivotal trials, with a once-daily oral application in the evening. Amantadine ER provides higher and more continuous amantadine plasma bioavailability than conventional immediate-release formulations, which require administration up to three times daily.

PND88 QUANTITATIVE RESEARCH IN PSYCHIATRY: CLINICAL UTILITY OF EXTENDED- AND IMMEDIATE-RELEASE FORMULATIONS OF AMANTADINE FOR DRUG-INDUCED EXTRAPYRAMIDAL REACTIONS

Anticholinergic medications are used to manage drug-induced extrapyramidal reactions (EPR), or movement disorders caused by antipsychotics and antidepressants. Long-term anticholinergic drug use is associated with increased cognitive impairment and dementia. An alternative to anticholinergics is amantadine hydrochloride, an N-methyl-D-aspartate antagonist receptor. This survey sought to gain psychiatrists’ insights on current therapeutic management of EPR, including amantadine immediate-release (IR) use, and the potential role of an amantadine extended-release (ER) formulation. This double-blind, quantitative survey of 98 US board-certified psychiatrists, mostly in private practice, who use amantadine IR to treat drug-induced EPR in adults was conducted between March and April 2018. Respondents were presented with amantadine ER pharmacokinetic data, reimbursement information, and a product profile. Respondents rated their views of amantadine IR in clinical use and their impression on the clinical utility of an amantadine ER formulation. Approximately 17% of patients treated by this group of psychiatrists experienced drug-induced EPR; patients with schizophrenia and schizoaffective disorder were most likely to be affected. Overall, 57% of patients who experience drug-induced EPR were treated with medication. Benztropine (44%) and amantadine (17%) were most commonly used to treat drug-induced EPR. Approximately 50% of patients started on amantadine IR experienced a benefit and remained on the therapy. When shown a product profile and attributes for amantadine ER, 93% of respondents anticipated prescribing the product. A majority of respondents would consider use of product in patients who could benefit from once daily dosing. Potential limitations of this survey include a limited number of respondents, underpowered for statistical significance, and a specific focus on amantadine-prescribing psychiatrists. The results of this survey reveal a majority of surveyed psychiatrists anticipate increased clinical utility of an amantadine ER formulation to treat drug-induced EPR. Of those who did not see clinical utility, cost was a common shared concern.

Extended-Release Amantadine for Levodopa-Induced Dyskinesia

ABSTRACTIntroduction: Levodopa-induced dyskinesia (LID) is a significant impediment to the long-term use of levodopa for Parkinson’s disease (PD). Relatively few studies exist that have described safe and effective therapy for LID. There is thus a significant need for therapy that can control LID to allow for greater sustainability of levodopa therapy. Amantadine extended release (ER) is currently the only FDA-approved medication for the treatment of LID. While other medications have demonstrated efficacy in treating the motor symptoms of PD, amantadine ER is the only one that has been shown, in several clinical trials, to reduce LID and reduce OFF time.Areas Covered: In this review, the authors present the findings of amantadine ER including its efficacy and safety. The authors also provide their expert perspectives on its use and its future prospects.Expert opinion: Several therapies are currently being used and studied for controlling LID, an unmet need in therapy for PD. Amantadine ER has potential to supplement levodopa therapy in PD and improve patient therapeutic outcomes.

Pharmacokinetic/Pharmacodynamic Correlation Analysis of Amantadine for Levodopa-Induced Dyskinesia.

Dyskinesia is a common motor complication associated with the use of levodopa to treat Parkinson's disease. Numerous animal studies in mice, rats, and nonhuman primates have demonstrated that the N-methyl-d-aspartate antagonist, amantadine, dose dependently reduces levodopa-induced dyskinesia (LID). However, none of these studies characterized the amantadine plasma concentrations required for a therapeutic effect. This study evaluates the pharmacokinetic (PK)/pharmacodynamic (PD) relationship between amantadine plasma concentrations and antidyskinetic efficacy across multiple species to define optimal therapeutic dosing. The PK profile of amantadine was determined in mice, rats, and macaques. Efficacy data from the 6-hydroxydopamine rat and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine macaque model of LID, along with previously published antidyskinetic efficacy data, were used to establish species-specific PK/PD relationships using a direct-effect maximum possible effect model. Results from the PK/PD model were compared with amantadine plasma concentrations and antidyskinetic effect in a phase 2 study in patients with Parkinson's disease treated with ADS-5102, an extended-release amantadine capsule formulation. Outcomes from each of the species evaluated indicate that the EC50 of amantadine for reducing dyskinesia range from 1025 to 1633 ng/ml (1367 ng/ml for an all-species model). These data are consistent with the mean amantadine plasma concentrations observed in patients with Parkinson's disease (∼1500 ng/ml) treated with ADS-5102 at doses that demonstrated a statistically significant reduction in dyskinesia. These results demonstrate that the EC50 of amantadine for reducing dyskinesia is consistent across multiple species and supports a plasma concentration target of ∼1400 ng/ml to achieve therapeutic efficacy.

Amantadine Extended-Release (GOCOVRI™): A Review in Levodopa-Induced Dyskinesia in Parkinson’s Disease

Amantadine extended-release (ER) capsules (GOCOVRI™) are approved in the USA for the treatment of dyskinesia in patients with Parkinson's disease (PD) receiving levodopa-based therapy, with or without concomitant dopaminergic medications. With a recommended dosage of 274mg once daily at bedtime, this new formulation of amantadine allows a more gradual time to peak plasma amantadine concentration and higher drug concentrations in the morning and throughout the day, the time period when levodopa-induced dyskinesia (LID) is the most problematic. In 13-week (EASE LID3) and 25-week (EASE LID), randomized, double-blind phase III trials, once-daily amantadine ER 274mg capsules significantly improved levodopa-induced dyskinesia (LID), while also increasing ON time without troublesome dyskinesia and reducing OFF time and ON time with troublesome dyskinesia from the morning and throughout the day, compared with placebo. In the ongoing, longer-term EASE LID2 study (with interim results reported for up to 64weeks), patients previously treated with amantadine ER maintained improvements in LID, as per patient-reported Unified Dyskinesia Rating Scale (UDysRS) scoring and ON/OFF times. Amantadine ER was generally well tolerated, with most adverse events (AEs) being transient and mild or moderate in severity. The most common (incidence >15%) treatment-related AEs in the placebo-controlled trials were hallucinations, dizziness, dry mouth and peripheral oedema. While long-term data are needed to establish durability of response and safety, including the completion of the ≈2-year EASE LID2 study, current evidence indicates that amantadine ER is an effective treatment option to consider in the management of LID in PD patients.

The role of extended-release amantadine for the treatment of dyskinesia in Parkinson's disease patients.

Levodopa is the most efficacious treatment for Parkinson's disease (PD). Long-term treatment with levodopa is limited due to dyskinesia. Dyskinesia in PD can be socially and functionally disabling. Extended-release amantadine (amantadine ER) is the first approved medication for the treatment of dyskinesia. When it is given at bedtime, it reaches plasma concentration approximately twice the level achieved by amantadine immediate release. Amantadine ER reduces the severity and duration of dyskinesia during the day, reduces OFF time and increases ON time without troublesome dyskinesia. The most common side effects are hallucination, dizziness, orthostatic hypotension and pedal edema. This review discusses the safety and efficacy of amantadine ER in dyskinesia in PD patients.

Amantadine Extended Release for Walking Impairment in Multiple Sclerosis

Better treatments are needed for gait disorders in patients with multiple sclerosis (MS). Amantadine extended-release was studied in a randomized,

Efficacy and safety of amantadine for the treatment of L-DOPA-induced dyskinesia.

L-DOPA induced dyskinesias (LIDs) may affect up to 40% of Parkinson's disease (PD) and impact negatively health-related quality of life. Amantadine has demonstrated significant antidyskinetic effects in animal PD models and in randomized double-blind placebo-controlled trials (RCTs) in patients with PD. These effects are thought to be related to the blockade of NMDA receptors modulating cortico-striatal glutamatergic-dopaminergic interactions involved in the genesis of LIDs. There are three pharmaceutical forms of amantadine currently available in the market: an oral immediate-release (IR) formulation, which is widely available; an extended-release (ER) formulation (ADS-5102) which has been recently developed and approved by the FDA; and an intravenous infusion (IV) solution, which is not commonly used in clinical practice. RCTs with amantadine IR or ER, involving more than 650 patients have shown consistent and long-lasting reductions in LIDs. Interestingly, ADS-5102 not only reduced LIDs, but also reduced significantly at the same time the duration of daily OFF-time, a unique finding compared with other antiparkinsonian medications that usually reduce time spent OFF at the cost of worsening of LIDs. Amantadine IR might also have possible effects on other PD symptoms such as apathy or fatigue. The most common adverse reactions with amantadine are constipation, cardiovascular dysfunction including QT prolongation, orthostatic hypotension and edema, neuropsychiatric symptoms such as hallucinations, confusion and delirium, nausea and livedo reticularis. Corneal degeneration is rare but critical. In summary, amantadine immediate and extended-release are effective and safe for the treatment of LIDs.

Extended-Release Amantadine—A Smart Pill for Treatment of Levodopa-Induced Dyskinesia but Does the Evidence Justify the Cost?

Extended-Release Amantadine—A Smart Pill for Treatment of Levodopa-Induced Dyskinesia but Does the Evidence Justify the Cost?

Current treatment and future prospects of dopa-induced dyskinesias.

Levodopa-induced dyskinesias (LID) are one of the main issues in the management of Parkinson's disease (PD); once these dyskinesias are established treatment becomes difficult, so preventive strategies should be first evaluated. Although levodopa (LD) treatment has recently been related as risk factor for LID, the main strategy to delay LID is to start PD treatment with dopamine agonists, adding LD at low doses. After LID onset, approaches include reducing single LD doses, reducing or discontinuing monoamine oxidase type B/catechol O-methyltransferase (MAO-B/COMT) inhibitors and extended-release (ER) LD. Amantadine represents the best antidyskinetic tool, and ER amantadine is the most promising upcoming antidyskinetic drug. New LD formulations such as IPX-066 (able to provide continuous dopaminergic stimulation) also represent promising new approaches. The involvement of a nondopaminergic system in the pathogenesis of LID suggests that the modulation of glutamate, serotonin and adenosine could have potential as new upcoming drug targets, but the role of such drugs will still need to be confirmed in randomized controlled trials.