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 jpet.118.247650
DO 10.1124/jpet.118.247650
A1 Elizabeth Brigham
A1 Tom Johnston
A1 Carl Brown
A1 Jonathon Holt
A1 Susan Fox
A1 Michael Hill
A1 Patrick Howson
A1 Jonathan Brotchie
A1 Jack Nguyen
YR 2018
UL http://jpet.aspetjournals.org/content/early/2018/08/07/jpet.118.247650.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 non-human primates have demonstrated that the NMDA 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-pharmacodynamic (PK/PD) relationship between amantadine plasma concentrations and antidyskinetic efficacy across multiple species to define optimal therapeutic dosing. The pharmacokinetic profile of amantadine was determined in mice, rats, and macaques. Efficacy data from the 6-OHDA-rat and MPTP-macaque model of LID, along with previously published antidyskinetic efficacy data, were used to establish species-specific PK/PD relationships using a direct effect Emax 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 50% effective plasma concentrations (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 provides a plasma concentration target of ~1400 ng/mL to achieve therapeutic efficacy.