A Quantitative Systems Pharmacology Model for Simulating Off-time in Augmentation Trials for Parkinson’s Disease. Application to Preladenant

The clinical impact of therapeutic interventions in Parkinson’s disease is often measured as a reduction in OFF-time when the beneficial effects of the standard-of-care L-DOPA formulations wanes off. We investigated the pharmacodynamic interactions of augmentation therapy to standard-of-care using a quantitative systems pharmacology (QSP) of the basal ganglia motor circuit, essentially a computer model of the different basal ganglia subregions with the appropriate connectivity and cell-specific expression of G-protein coupled receptors. The calculated beta/gamma power spectrum of the local field potentials in the subthalamic nucleus was previously calibrated on a UPDRS scale. We combine this QSP model with PK modeling of different formulations of L-DOPA and the adenosine 2A antagonist preladenant to predict the liability of OFF-time, non-troublesome and troublesome dyskinesia. Model calibration with clinical observations showed favorable correlations. Simulations show that augmentation with the adenosine A 2A antagonist preladenant reduces in OFF-time ranges between 6 minutes for Rytary 950 mg 5-times daily and 37 minutes for 100 mg L-DOPA – 3 or 5 times daily. Exploring delays between preladenant and L-DOPA intake did not improve the outcome. A 2A antagonists with an ideal PK and pharmacology profile can achieve range from 9.5 minutes with DuoDopa to 55 minutes with low dose L-DOPA formulations. There is a strong non-linear relationship between drug exposure and clinical efficacy. With the development of digital wearables for real-time estimation of clinical outcome, this predictive approach can support both the design of clinical trials with new therapeutic agents and the optimization of combination therapy in clinical practice.