RT Journal Article SR Electronic T1 Pharmacokinetic/Pharmacodynamic Correlation Analysis of Amantadine for Levodopa-Induced Dyskinesia JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 373 OP 381 DO 10.1124/jpet.118.247650 VO 367 IS 2 A1 Elizabeth F. Brigham A1 Tom H. Johnston A1 Carl Brown A1 Jonathon D. S. Holt A1 Susan H. Fox A1 Michael P. Hill A1 Patrick A. Howson A1 Jonathan M. Brotchie A1 Jack T. Nguyen YR 2018 UL http://jpet.aspetjournals.org/content/367/2/373.abstract AB 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.