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
N-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 EC50 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 EC50 of
amantadine for reducing
dyskinesia is consistent across multiple species and supports a plasma concentration target of ∼1400 ng/ml to achieve therapeutic efficacy.