Dataset Information

Pharmacokinetics of ADS-5102 (Amantadine) Extended Release Capsules Administered Once Daily at Bedtime for the Treatment of Dyskinesia.

ABSTRACT:

Background

Preclinical and clinical studies suggest amantadine immediate-release (IR) may reduce dyskinesia in Parkinson's disease (PD), although higher doses are associated with increased CNS adverse events (AEs). ADS-5102 is an extended release amantadine capsule formulation, designed for once-daily dosing at bedtime (qhs) to provide high concentrations upon waking and throughout the day, with lower concentrations in the evening. The pharmacokinetics (PK) of ADS-5102 were assessed in two phase I studies in healthy subjects, and a blinded, randomized phase II/III dose-finding study in PD patients.

Methods

The first phase I study assessed single ADS-5102 doses (68.5, 137, and 274 mg) in a crossover design, whereas the second phase I study evaluated ADS-5102 137 mg for 7 days followed by amantadine IR 81 mg twice daily (or reverse order). In the phase II/III double-blind study, PD patients with dyskinesia were randomized to ADS-5102 (210, 274, or 338 mg) or placebo for 8 weeks.

Results

Single ADS-5102 doses resulted in a slow initial rise in amantadine plasma concentration, with delayed time to maximum concentration (12-16 h). Amantadine plasma concentrations were higher in PD patients versus healthy volunteers. The steady-state profile of once-daily ADS-5102 was significantly different from that of twice-daily amantadine IR, such that the two formulations are not bioequivalent. PK modeling suggested the recommended daily ADS-5102 dosage (274 mg qhs) resulted in 1.4- to 2.0-fold higher amantadine plasma concentrations during the day versus amantadine IR.

Conclusions

ADS-5102 can be administered once-daily qhs to achieve high amantadine plasma concentrations in the morning and throughout the day, when symptoms of dyskinesia occur.

SUBMITTER: Hauser RA

PROVIDER: S-EPMC6325984 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundAlthough levodopa is considered the most effective pharmacotherapy for motor symptoms of Parkinson's disease (PD), chronic use is associated with motor complications, including fluctuating response and unpredictable, involuntary movements called dyskinesia. ADS-5102 (amantadine) extended-release (ER) capsules (GOCOVRITM) is a recent US FDA-approved treatment for dyskinesia in PD patients. ADS-5102 is a high-dose, ER formulation of amantadine, administered orally once daily at bedtime, that achieves high plasma drug concentrations throughout the day.ObjectiveIn this study, we present pooled results from two randomized, double-blind, placebo-controlled, phase III ADS-5102 trials.Patients and methodsThe two studies in PD patients with dyskinesia shared design and eligibility criteria, differing only in treatment duration. Results from common assessment time points were pooled.ResultsAt 12 weeks, the least squares (LS) mean change in total score on the Unified Dyskinesia Rating Scale among 100 patients randomized to ADS-5102 and 96 patients randomized to placebo was - 17.7 (standard error [SE] 1.3) vs. - 7.6 (1.3) points, respectively (- 10.1 points, 95% confidence interval [CI] - 13.8, - 6.5; p < 0.0001). The relative treatment difference between groups was 27.3% (p < 0.0001). At 12 weeks, the LS mean change in OFF time was - 0.59 (0.21) vs. +0.41 (0.20) h/day, a difference of - 1.00 h/day (95% CI - 1.57, - 0.44; p = 0.0006). For both efficacy measures, a significant difference from placebo was attained by two weeks, the first post-baseline assessment, and was maintained throughout 12 weeks. In the pooled ADS-5102 group, the most common adverse events were hallucination, dizziness, dry mouth, peripheral edema, constipation, falls, and orthostatic hypotension.ConclusionsThese analyses provide further evidence supporting ADS-5102 as an adjunct to levodopa for treating both dyskinesia and OFF time in PD patients with dyskinesia. Clinicaltrials.gov identifier: NCT02136914 and NCT02274766.

Project description:ImportanceMedical treatment of levodopa-induced dyskinesia (LID) in Parkinson disease (PD) is an unmet need.ObjectiveTo evaluate the efficacy and safety of ADS-5102 (amantadine) extended-release 274-mg capsules for treatment of LID in patients with PD.Design, setting, and participantsA randomized, double-blind, placebo-controlled clinical trial was conducted between May 7, 2014, and July 22, 2015, at 44 North American sites among patients with PD treated with levodopa who experienced at least 1 hour of troublesome dyskinesia per day with at least mild functional impact.InterventionsPatients were randomized to receive placebo or 274 mg of ADS-5102 administered orally at bedtime for up to 25 weeks.Main outcomes and measuresThe primary efficacy analysis was the change from baseline to week 12 in the Unified Dyskinesia Rating Scale total score for ADS-5102 vs placebo in the modified intent-to-treat population. OFF time (amount of time the PD medication is not controlling motor symptoms) was a key secondary end point. Safety analyses included all patients who received the study drug (ADS-5102 or placebo).ResultsA total of 189 patients were screened, and 126 were randomized; the modified intent-to-treat population included 121 patients (51 women and 70 men; mean [SD] age, 64.7 [9.1] years). At week 12, the least-squares mean (SE) change in the Unified Dyskinesia Rating Scale score was -15.9 (1.6) for ADS-5102 (n = 63) and -8.0 (1.6) for placebo (n = 58) (treatment difference, -7.9; 95% CI, -12.5 to -3.3; P < .001). OFF time decreased by a mean (SE) of 0.6 (0.3) hours for ADS-5102 and increased by 0.3 (0.3) hours for placebo (treatment difference, -0.9 hours; 95% CI, -1.6 to -0.2; P = .02). Common adverse events for ADS-5102 vs placebo included visual hallucinations (15 [23.8%] vs 1 [1.7%]), peripheral edema (15 [23.8%] vs 0), and dizziness (14 [22.2%] vs 0). Adverse events led to treatment discontinuation for 13 patients receiving ADS-5102 (20.6%) vs 4 patients receiving placebo (6.9%).Conclusions and relevanceADS-5102, 274 mg at bedtime, may be an effective treatment for LID. An additional benefit is reduced OFF time. To our knowledge, this is the first demonstration of an oral treatment reducing both LID and OFF time in patients with PD with dyskinesia.Trial registrationclinicaltrials.gov Identifier: NCT02136914.

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Project description:IntroductionGocovri (amantadine) extended release capsules are approved for treatment of dyskinesia and as a levodopa adjunct for OFF episodes in patients with Parkinson's disease (PD). We report treatment-related effects on non-motor symptoms (NMS) assessed as secondary outcomes in two trials using the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part I.MethodsEASE LID and EASE LID 3 enrolled levodopa-treated patients with PD and ≥ 1 h/day ON time with troublesome dyskinesia. Patients were randomized to Gocovri (274 mg) or placebo taken daily at bedtime. Treatment differences from baseline to week 12 in MDS-UPDRS Part I were evaluated for the pooled population (N = 196) from both trials. Correlation analyses of NMS (MDS-UPDRS Part I) with dyskinesia using Unified Dyskinesia Rating Scale (UDysRS) scores were performed.ResultsFor changes in the MDS-UPDRS Part I items, the treatment difference favored Gocovri in daytime sleepiness (P = 0.006) and depression (P = 0.049) scores, but favored placebo in cognitive impairment (P = 0.038), and hallucinations and psychosis (P < 0.001) scores. The treatment difference for the changes in total Part I score was -0.8, favoring Gocovri (P = 0.22). At baseline, MDS-UPDRS Part I modestly correlated with UDysRS score (r +0.25, P < 0.001), and improvement in NMS correlated with improvement in dyskinesia at week 12 for Gocovri (r +0.39, P < 0.001) but not placebo (r +0.12, P = 0.29). The most commonly reported adverse events for Gocovri were hallucination (21%); dizziness, dry mouth, and peripheral edema (16% each); and constipation, falls, and orthostatic hypotension (13% each).ConclusionThis post hoc analysis shows potential benefit with Gocovri treatment for the NMS of daytime sleepiness and depression in dyskinetic PD patients. Overall, improvement in NMS scores correlated with improvement in dyskinesia.Trial registrationClinicalTrials.gov identifiers: NCT02136914 and NCT02274766.