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

Early research suggested dyskinesia reduction with amantadine is significantly related to plasma concentration. 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.

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.

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).