title: Pharmacokinetics and metabolism of [14C]-tozadenant (SYN-115), a novel A2a receptor antagonist ligand, in healthy volunteers.
abstract: 1. This phase-I study (NCT02240290) was designed to investigate the human absorption, disposition and mass balance of14C-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 Cmaxof tozadenant was 1.74 μg/mL and AUC(0-t)35.0 h μg/mL, t1/215 h, Vz/F 1.82 L/kg and CL/F 1.40 mL/min/kg. For total [14C] radioactivity, the Cmaxwas 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.
authors.affiliation: a Department of Non Clinical Development , UCB Pharma , Braine l'Alleud , Belgium.
authors.forename: Valérie
authors.initials: V
authors.lastname: Mancel
authors.affiliation: a Department of Non Clinical Development , UCB Pharma , Braine l'Alleud , Belgium.
authors.forename: François-Xavier
authors.initials: FX
authors.lastname: Mathy
authors.affiliation: a Department of Non Clinical Development , UCB Pharma , Braine l'Alleud , Belgium.|b Department of Quality Assurance R&D , GSK Vaccines , Rixensart , Belgium.
authors.forename: Pierre
authors.initials: P
authors.lastname: Boulanger
authors.affiliation: c Department of Science and Technology , Xceleron Inc , Germantown , MD , USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: English
authors.affiliation: c Department of Science and Technology , Xceleron Inc , Germantown , MD , USA.
authors.forename: Marie
authors.initials: M
authors.lastname: Croft
authors.affiliation: d Department of Clinical Development , Biotie Therapies Inc , South San Franscisco , CA , USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Kenney
authors.affiliation: e Department of Non Clinical Development , Biotie Therapies Inc , South San Franscisco , CA , USA.
authors.forename: Tarra
authors.initials: T
authors.lastname: Knott
authors.affiliation: f Department of Quantitative Clinical Pharmacology , UCB Pharma , Braine l'Alleud, , Belgium.
authors.forename: Armel
authors.initials: A
authors.lastname: Stockis
authors.affiliation: f Department of Quantitative Clinical Pharmacology , UCB Pharma , Braine l'Alleud, , Belgium.
authors.forename: Massimo
authors.initials: M
authors.lastname: Bani
mesh_terms: D000284:Administration, Oral; D000328:Adult; D052160:Benzothiazoles / Q000493:pharmacokinetics*; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D005243:Feces / Q000737:chemistry; D006207:Half-Life; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D053719:Tandem Mass Spectrometry
chemical_list: D052160:Benzothiazoles; C000593256:tozadenant
keywords: ADME; LC-MS/MS; Parkinson; accelerator mass spectrometry; human; radioactivity