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Abstract
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 Cmax of tozadenant was 1.74 μg/mL and AUC(0–t) 35.0 h μg/mL, t1/2 15 h, Vz/F 1.82 L/kg and CL/F 1.40 mL/min/kg. For total [14C] radioactivity, the Cmax 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.
Declaration of interest
VM, FXM, AM and MB are current employees of UCB Pharma. PB was an employee of UCB Pharma at the time that this work was conducted and is a current employee of GSK Vaccines Belgium. SE and MC are current employees of Xceleron Inc. CK and TK are current employees of Biotie Therapies Inc.