An open-label, positron emission tomography study to assess adenosine A2A brain receptor occupancy of vipadenant (BIIB014) at steady-state levels in healthy male volunteers.

Objective: Adenosine A 2A receptor antagonists are potential new treatments for Parkinson disease. We used positron emission tomography (PET) of the A 2A receptor radiotracer, [ 11 C]SCH442416, to assess binding of the novel A 2A antagonist, vipadenant (previously known as BIIB014), to human brain A 2A receptors and to investigate the relationship among dose, steady-state plasma levels, and receptor occupancy. Methods: We used PET to compare ["C]SCH442416 uptake before and after blockade with daily oral vipadenant (2.5―100 mg/d for 10 or 11 days) in healthy volunteers (n = 15). We estimated receptor occupancy in brain regions of interest, particularly the putamen, by kinetic modeling of PET data. We estimated the dose, minimal plasma concentration at steady state (C min ), and area under the plasma concentration curve (AUC 0-τ ) at the steady state required for saturation (≥90% receptor occupancy) using Bayesian Emax and logistic regression models. Results: The estimated receptor occupancy of vipadenant in the brain regions of interest varied from 74% to 94% at the lowest daily dose (2.5 mg) and reached saturation in all regions at 100 mg. In the putamen, the estimated minimal daily dose, steady-state C min , and steady-state AUC 0-τ required for receptor saturation were 10.2 mg (interquartile range, 28%), 0.097 μg/mL (27%), and 6 μg h/mL (21%), respectively. Conclusions: This study provides the first evidence that vipadenant occupies A 2A receptors in the human brain. Receptor occupancy was related to both dose and plasma levels of vipadenant. These results, coupled with previous efficacy results in animals, justify continued development of vipadenant as a potential treatment for Parkinson disease.