Pharmacokinetics and metabolism of [14C]-tozadenant (SYN-115), a novel A2a receptor antagonist ligand,in healthy volunteers

1.?This phase-I study (NCT02240290) was designed to investigate the human absorption, disposition and mass balance of ¹⁴C-tozadenant, a novel A2a receptor antagonist in clinical development for Parkinson s disease.

2.?Six healthy male subjects received a single oral dose of tozadenant (240?mg containing 81.47?KBq of ¹⁴C]-tozadenant). Blood, urine and feces were collected over 14 days. Radioactivity was determined by liquid scintillation counting or accelerator mass spectrometry (AMS). Tozadenant and metabolites were characterized using HPLC-MS/MS and HPLC-AMS with fraction collection.

3.?At 4?h, the C_max of tozadenant was 1.74?μg/mL and AUC_(0–t) 35.0?h?μg/mL, t_1/2 15?h, Vz/F 1.82?L/kg and CL/F 1.40?mL/min/kg. For total ¹⁴C] radioactivity, the C_max was 2.29?μg?eq/mL at 5?h post-dose and AUC_(0–t) 43.9?h?μg?eq/mL. Unchanged tozadenant amounted to 93% of the radiocarbon AUC_(0–48h). At 312?h post-dose, cumulative urinary and fecal excretion of radiocarbon reached 30.5% and 55.1% of the dose, respectively. Unchanged tozadenant reached 11% in urine and 12% of the dose in feces. Tozadenant was excreted as metabolites, including di-and mono-hydroxylated metabolites, N/O dealkylated metabolites, hydrated metabolites.

4.?The only identified species circulating in plasma was unchanged tozadenant. Tozadenant was primarily excreted in urine and feces in the form of metabolites.