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

Hauser, Robert A.; Pahwa, Rajesh; Wargin, William A.; Souza-Prien, Cindy; McClure, Natalie; Johnson, Raymond L.; Nguyen, Jack; Patni, Rajiv; Went, Gregory T.

doi:10.1007/s40262-018-0663-4

Cited by 36 publications

(37 citation statements)

References 22 publications

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“…Improvements in continuous delivery of amantadine would provide a smooth PK profile achieving high concentrations and better coverage throughout the day compared with the peaks and troughs associated with bolus dosing. As reported in the study by Hauser et al (2018), ADS-5102 can be dosed once daily at bedtime to achieve high morning and sustained daytime amantadine plasma concentrations when symptoms of dyskinesia occur. PK modeling suggested the recommended daily ADS-5102 dosage (274 mg once daily at bedtime) provided maximum steady-state concentrations of ∼1500 ng/ml in patients with Parkinson's disease, which is approximately 2-fold higher than that achieved with amantadine IR dosing (81 mg, equivalent to amantadine HCl 100 mg, administered at 8:00 AM and 4:00 PM, based on prescription data, which indicated that ∼85% of patients with Parkinson's disease treated with amantadine IR were prescribed a dose of #161 mg/day) (Navarro et al, 2017).…”

Section: Discussionmentioning

confidence: 96%

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

Brigham

Johnston

Brown

et al. 2018

J Pharmacol Exp Ther

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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 -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 EC 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 EC of amantadine for reducing dyskinesia is consistent across multiple species and supports a plasma concentration target of ∼1400 ng/ml to achieve therapeutic efficacy.

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Section: Discussionmentioning

confidence: 96%

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

Brigham

Johnston

Brown

et al. 2018

J Pharmacol Exp Ther

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“…All of these ADLs are known to be affected by the parkinsonian state. Since UDysRS Part 1B instructs a patient to rate the impact of "jerking or twisting movements" occurring "when your Parkinson's disease medications were working" [22], the findings show that the ADLs are specifically worsened by dyskinesia in its typical forms.…”

Section: Discussionmentioning

confidence: 99%

“…It is the only medication approved by the United States Food and Drug Administration for this use [21]. ADS-5102 dosed at bedtime provides high plasma amantadine concentrations upon waking and throughout the day, with lower concentrations in the evening [22]. In dyskinetic PD patients, both of two pivotal phase 3 clinical trials of ADS-5102 (EASE LID [23] and EASE LID 3 [24]) demonstrated a reduction of dyskinesia, as measured by the primary endpoint (total score at Week 12 on the Unified Dyskinesia Rating Scale, the UDysRS [25,26]).…”

Section: Introductionmentioning

confidence: 99%

Impact of dyskinesia on activities of daily living in Parkinson's disease: Results from pooled phase 3 ADS-5102 clinical trials

Pahwa

Isaacson²,

Jimenez-Shaheed

et al. 2019

Parkinsonism & Related Disorders

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In Parkinson's disease, dyskinesias result from disease progression and chronic levodopa therapy. Using Unified Dyskinesia Rating Scale (UDysRS) data pooled from two pivotal trials of ADS-5102 (amantadine) extended-release capsules in dyskinetic patients, we assessed the impact of dyskinesia on activities of daily living (ADLs), and the effects of ADS-5102 versus placebo. Methods: Patients had troublesome dyskinesia (≥1 h/day) and at least mild functional impact of dyskinesia per Movement Disorder Society Unified Parkinson's Disease Rating Scale, Part IV, item 4.2. UDysRS Parts 1B, 3, and 4 scores at baseline were summarized descriptively. Twelve-week changes in score distributions and total scores were tested for significant differences between treatments. Results: Among 196 patients, the majority (63%-73%) characterized their dyskinesia at baseline as having at least a mild impact on walking and balance; public and social settings; exciting or emotional settings; doing hobbies and other activities; handwriting; and dressing (six of ten ADLs in UDysRS Part 1B). By clinician ratings (in Parts 3 and 4), greatest impairment was most often observed in the trunk (62% of patients) and occurred most often for the ADL of dressing (64% had at least moderate impairment). ADS-5102 significantly reduced the patient-rated impact of dyskinesia on six of ten ADLs in Part 1B, the clinician-rated intensity of dyskinesia in all seven body regions assessed in Part 3, and the clinician-rated disability during three of four ADL tasks assessed in Part 4. Improvements in Parts 1B, 3, and 4 total scores were also statistically significant. Conclusion: Dyskinesia can impair multiple tasks of daily living. Further studies may help characterize its underreported impact. By several measures, ADS-5102 treatment was associated with significant improvement of dyskinesias.

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“…ADS‐5102 (amantadine) extended release capsules (GOCOVRI™), a novel formulation of amantadine, were designed to deliver a distinct concentration‐time profile of amantadine that is not achievable with amantadine IR. With bedtime dosing of ADS‐5102, its initial slow rise in plasma concentration overnight achieves twice the plasma level (∼1500 ng/mL) of a standard dose of amantadine IR, 100 mg bid during the early morning and throughout the day . The once‐daily dosing regimen of ADS‐5102 may also provide enhanced convenience compared with multiple dosing of amantadine IR.…”

Section: Introductionmentioning

confidence: 99%

“…With bedtime dosing of ADS-5102, its initial slow rise in plasma concentration overnight achieves twice the plasma level (1500 ng/mL) of a standard dose of amantadine IR, 100 mg bid during the early morning and throughout the day. 19 The once-daily dosing regimen of ADS-5102 may also provide enhanced convenience compared with multiple dosing of amantadine IR.…”

Section: Introductionmentioning

confidence: 99%

Parkinson's Patients with Dyskinesia Switched from Immediate Release Amantadine to Open‐label ADS‐5102

Isaacson

Fahn

Pahwa

et al. 2018

Movement Disord Clin Pract

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BackgroundADS‐5102 (amantadine) extended release capsules (GOCOVRI™) are a treatment for dyskinesia in patients with Parkinson's disease (PD). ADS‐5102 reduced dyskinesia and OFF time in phase 3 controlled trials of up to six months. Amantadine immediate release (IR) is used for dyskinesia, but suboptimal durability and tolerability limit its clinical utility.MethodsIn an ongoing, open‐label, phase 3 study in the US and Western Europe (NCT02202551), patients with PD received 274 mg of ADS‐5102 (equivalent to 340 mg amantadine HCl) once daily at bedtime for up to two years. Study outcomes included safety and assessment of motor complications, as measured by the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS‐UPDRS) Part IV. This manuscript focuses on those patients switched to ADS‐5102 from amantadine IR. Results in two groups of patients who previously completed a randomized controlled trial (EASE LID or EASE LID 3) are also presented according to use of ADS‐5102 or placebo in that study before enrollment in the open‐label study.ResultsChange in MDS‐UPDRS Part IV at week 8 was –0.3 in the previous ADS‐5102 subgroup (n = 61), –3.4 in the previous placebo subgroup (n = 79), and –3.4 in the previous amantadine IR subgroup (n = 32). Effects were maintained to week 64. In the previous amantadine IR subgroup (mean treatment duration, 2.5 years), mean amantadine IR dose was 221 mg. Safety data were consistent with previous randomized controlled trials of ADS‐5102.ConclusionThese open‐label data suggest ADS‐5102 provides incremental reduction from baseline in MDS‐UDPRS Part IV score in patients switched directly from amantadine IR, without exacerbating adverse events.

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

Cited by 36 publications

References 22 publications

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

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

Impact of dyskinesia on activities of daily living in Parkinson's disease: Results from pooled phase 3 ADS-5102 clinical trials

Parkinson's Patients with Dyskinesia Switched from Immediate Release Amantadine to Open‐label ADS‐5102

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