Objective: This study was designed to assess the reproducibility of the amantadine anti-dyskinetic effect in the MPTP L-DOPA-Induced Dyskinesia (LID) macaque model for soundly defining the sample sizes required to test anti-dyskinetic compounds.

Background: Dyskinesia are side effects associated with chronic L-dopa treatment in Parkinson’s patients that are partially alleviated by the weak NMDA antagonist amantadine. Although the current benchmark, response to amantadine is variable and effective only in a subset of patients. While recognizing that the MPTP macaque model is the gold-standard pre-clinical translational model, we provide critical information for designing and powering studies for testing of novel anti-dyskinetic strategies.

Methods: We conducted the meta-Analysis of 11 studies (n ranging from 7 to 24 individuals) involving NHPs treated with vehicle and amantadine in combination with levodopa. The effect was calculated by the difference in total dyskinesia score between amantadine and vehicle. The primary objective was to quantify the reproducibility of the study responses and to understand the variability present between studies and between animals within the studies. Secondly, we determined the expected effect size and variation to ensure appropriate statistical design and power for future studies with new compounds.

Results: The mean profiles over all animals in all studies show a reasonable efficacy window between vehicle and amantadine response profiles. However, the profiles in individual studies are less consistent. The meta-analysis of the effect suggested a study-to-study heterogeneity (effect from -2.6 ± 1.45 to -15.3 ±1.03). The meta-analysis of the within-subject standard deviation suggested that the heterogeneity between-study is negligible relative to the size of the variability within-study. From the two meta-analyses, we obtained an estimate of the ‘average’ amantadine effect of -8.8 and an estimate of the potential size of the within-subject SD of 3.6. The number of animals required to detect 100%, 67% and 50% of the amantadine effect is 4, 6 and 12 with the corresponding power of 85%, 84% and 83% respectively.

Conclusions: Result of this meta-analysis is of significance and confirms that the MPTP macaque model is a reliable translational model to assess the antidyskinetic ability of a novel mechanism. However, due to the intersubject variability using suitable sample size is essential to obtain consistent results.

« Back to 2018 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/quantifying-the-reproducibility-of-an-in-vivo-assay-examination-of-historical-amantadine-effects-in-the-macaque-model-of-l-dopa-induced-dyskinesia/