Extended-Release Amantadine Shows Reduction in Dyskinesia Severity for Parkinson Disease

In a pharmacokinetic/pharmacodynamic (PK/PD) analysis presented at the 2024 International Congress of Parkinson’s Disease and Movement Disorders, held September 27 to October 1, in Philadelphia, Pennsylvania, findings revealed a significant association between plasma concentrations of extended-release amantadine (Gocovri; Supernus) and reductions of dyskinesia severity in patients with Parkinson disease (PD).¹ These results suggest that dyskinesia reduction with amantadine is significantly related to plasma concentration, confirming prior research.²

In the PK/PD model, researchers included steady-state data from 272 patients (mean age, 65 years; weight, 77 kg; creatinine clearance, 98 mg/dL) who received nightly doses of placebo (n = 117), or 210 mg (n = 18), 274 mg (n = 120), or 338 mg (n = 17) extended-release amantadine. Investigators reported that in the linear regression analysis, results demonstrated statistically significant PK/PD relationships between amantadine exposure measures (Cmax, Cave, Cmin and AUC) and reductions in the Unified Dyskinesia Rating Scale (UDysRS) total score as well as the UDysRS ON-state dyskinesia component scores (Parts 1a, 1b, 3 and 4).

Presented by coauthor Robert A. Hauser, MD, MBA, director of the Parkinson’s and Movement Disorders Center at the University of South Florida, and colleagues, the PK/PD model was justified using data from one phase 2 trial and two phase 3 trials. Researchers used a linear regression analysis to compare amantadine concentrations, which were mimicked utilizing a previously developed population PK model, with the changes from baseline in the UDysRS total score and component scores (Parts 1-4). Per each study, investigators noted that UDysRS assessments were arranged to happen at anticipated periods of dyskinesia, at least 30-minutes after levodopa use, at approximately the same time of day for each participant.

A pooled phase 3 data previously presented at the 2nd Annual Advanced Therapeutics in Movement and Related Disorders (ATMRD) Congress, held by the PMD Alliance from June 8-11, 2023, in Washington, DC, by Hauser and colleagues revealed that the use of extended-related amantadine for patients with PD might offer clinicians an ability to increase the predictability of good ON time from day to day.³ All told, the least-squares mean change from baseline in predictable good ON hours per day in paired intervals was significant at all time points for those on extended-release amantadine (n = 100) compared with those on placebo (n = 96).

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For those on amantadine, these changes were 4.3 hours at week 2 (mixed models for repeated measures treatment effect, 2.8; P <.0001), 5.05 hours at week 8 (treatment effect, 2.9; P <.0001), and 4.9 hours at week 12 (treatment effect, 2.95; P <.0001); comparatively, those on placebo recorded changes of 1.5 hours, 2.1 hours, and 1.95 hours, respectively. In an analysis of covariance for weeks 8 and 12 combined, the change for the treatment group was 2.6 hours compared with –0.85 hours for those on placebo (treatment effect, 3.4; P <.0001).

Good ON time over the course of the waking day was calculated by tallying the percentage of matched diary intervals that were concordant for good ON and dividing this percentage by the number of matched intervals where neither interval was recorded when the patient was sleeping. Participants recorded their predominant motor state in their home diaries in 30-minute intervals over the course of 2 consecutive days.

At baseline, patients in the amantadine group reported a mean OFF time of 3.0 hours (SD, 2.3) and those in the placebo group reported 2.6 hours (SD, 2.0). The percentage of concordance for good ON time was 31.0% (SD, 18.5) for the amantadine group and 31.5% (SD, 18.1) for the placebo group. Notably, this rate included only 98 of 100 patients in the treatment arm.

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REFERENCES
1. Z. Wang, R. Gomeni, R. Pahwa, R. Hauser, A. Formella, M. Grall, H. Upadhyaya, J. Rubin. Pharmacokinetic-Pharmacodynamic Modeling of Amantadine Extended-Release Capsule Effects on Dyskinesia in Parkinson Disease [abstract]. Mov Disord. 2024; 39 (suppl 1). https://www.mdsabstracts.org/abstract/pharmacokinetic-pharmacodynamic-modeling-of-amantadine-extended-release-capsule-effects-on-dyskinesia-in-parkinson-disease/. Accessed September 30, 2024.
2. Verhagen Metman L, Del Dotto P, van den Munckhof P, Fang J, Mouradian MM, Chase TN. Amantadine as treatment for dyskinesias and motor fluctuations in Parkinson's disease. Neurology. 1998;50(5):1323-1326. doi:10.1212/wnl.50.5.1323
3. Hauser RA, Formella AE, Qin OP, Grall MS. Predictability of GOOD ON Time During the Waking Day with Amantadine Extended-Release Capsules A Post-hoc Analysis of Pooled Pivotal Trials. Presented at: ATMRD; June 9-11, 2023; Washington, DC.