Objective: Evaluate pharmacokinetic/pharmacodynamic (PK/PD) relationships for the delayed- and extended-release (DR/ER) capsule formulation of amantadine [1] in the treatment of levodopa-related dyskinesia in Parkinson disease.

Background: Early research suggested dyskinesia reduction with amantadine is significantly related to plasma concentration [2]. Amantadine extended release (ER) capsules are specifically approved for the treatment of levodopa-related dyskinesia and OFF episodes; this once‑daily, bedtime-administered dosage form has a DR/ER drug release profile and provides high amantadine concentrations that peak around the time of first morning levodopa dose.

Method: The PK/PD model was validated using data from one phase 2 and two phase 3 clinical trials. Linear regression analysis was used to compare amantadine concentrations (simulated using a previously developed population PK model) with changes from baseline in the Unified Dyskinesia Rating Scale (UDysRS) total score and component (Parts 1-4) scores.  For each trial, UDysRS assessments were scheduled to occur during anticipated periods of dyskinesia (at least 30-minutes following levodopa use), at approximately the same time of day for each patient.

Results: The model included steady-state data from 272 patients (mean age: 65 y, weight: 77 kg, creatinine clearance: 98 mg/dL), receiving nightly doses of placebo (n=117), or 210 mg (n=18), 274 mg (n=120), or 338 mg (n=17) amantadine ER. Linear regression analysis showed statistically significant PK/PD relationships between amantadine exposure measures (Cmax, Cave, Cmin and AUC) and reductions in the UDysRS total score, as well as the UDysRS ON-state dyskinesia component scores (Parts 1a, 1b, 3 and 4).

Conclusion: PK/PD modelling for amantadine ER capsules consistently showed a robustly significant relationship between plasma concentration and UDysRS ON-state dyskinesia measures.

References: [1] Gocovri (amantadine) extended release capsules. Prescribing Information. Emeryville, CA: Adamas Pharma, LLC; 2021.
[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 May;50(5):1323-6. doi: 10.1212/wnl.50.5.1323. PMID: 9595981.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/pharmacokinetic-pharmacodynamic-modeling-of-amantadine-extended-release-capsule-effects-on-dyskinesia-in-parkinson-disease/