Metabolism and disposition in rats, dogs, and humans of erdafitinib, an orally administered potent pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor
Creators: name: Scheers, Ellen
name: Borgmans, Carine
name: Keung, Chi
name: Bohets, Hilde
name: Wynant, Inneke
name: Poggesi, Italo
name: Cuyckens, Filip
name: Leclercq, Laurent
name: Mamidi, Rao N. V. S.
Publisher: name: Taylor & Francis
Year: 2024
Subjects: subject: Biochemistry
subject: Microbiology
subject: FOS: Biological sciences
subject: Cell Biology
subject: Genetics
subject: Neuroscience
subject: Physiology
subject: Pharmacology
subject: Geology
subject: FOS: Earth and related environmental sciences
subject: Chemical Sciences not elsewhere classified
subject: Immunology
subject: FOS: Clinical medicine
subject: Marine Biology
subject: Cancer
subject: Science Policy
subject: Mental Health
subject: Hematology
subject: Infectious Diseases
subject: FOS: Health sciences
subject: Computational Biology

description: This article describes <i>in vivo</i> biotransformation and disposition of erdafitinib following single oral dose of <sup>3</sup>H-erdafitinib and <sup>14</sup>C-erdafitinib to intact and bile duct-cannulated (BC) rats (4 mg/kg), <sup>3</sup>H-erdafitinib to intact dogs (0.25 mg/kg), and <sup>14</sup>C-erdafitinib to humans (12 mg; NCT02692677).Peak plasma concentrations of total radioactivity were achieved rapidly (<i>T</i><sub>max</sub>: animals, 1 h; humans, 2–3 h). Recovery of drug-derived radioactivity was significantly slower in humans (87%, 384 h) versus animals (rats: 91–98%, 48 h; dogs: 81%, 72 h). Faeces was the primary route of elimination in intact rats (95%), dogs (76%), and humans (69%); and bile in BC rats (48%). Renal elimination of radioactivity was relatively low in animals (2–12%) versus humans (19%).Unchanged erdafitinib was major component in human excreta (faeces, 17%; urine, 11%) relative to animals. M6 (O-desmethyl) was the major faecal metabolite in humans (24%) and rats (intact, 46%; BC, 11%), and M2 (O-glucuronide of M6) was the prevalent biliary metabolite in rats (14%). In dogs, besides M6, majority of radioactive dose in faeces was composed of multiple minor metabolites.In humans, unchanged erdafitinib was the major circulating entity. O-demethylation of erdafitinib was the major metabolic pathway in humans and animals. This article describes <i>in vivo</i> biotransformation and disposition of erdafitinib following single oral dose of <sup>3</sup>H-erdafitinib and <sup>14</sup>C-erdafitinib to intact and bile duct-cannulated (BC) rats (4 mg/kg), <sup>3</sup>H-erdafitinib to intact dogs (0.25 mg/kg), and <sup>14</sup>C-erdafitinib to humans (12 mg; NCT02692677). Peak plasma concentrations of total radioactivity were achieved rapidly (<i>T</i><sub>max</sub>: animals, 1 h; humans, 2–3 h). Recovery of drug-derived radioactivity was significantly slower in humans (87%, 384 h) versus animals (rats: 91–98%, 48 h; dogs: 81%, 72 h). Faeces was the primary route of elimination in intact rats (95%), dogs (76%), and humans (69%); and bile in BC rats (48%). Renal elimination of radioactivity was relatively low in animals (2–12%) versus humans (19%). Unchanged erdafitinib was major component in human excreta (faeces, 17%; urine, 11%) relative to animals. M6 (O-desmethyl) was the major faecal metabolite in humans (24%) and rats (intact, 46%; BC, 11%), and M2 (O-glucuronide of M6) was the prevalent biliary metabolite in rats (14%). In dogs, besides M6, majority of radioactive dose in faeces was composed of multiple minor metabolites. In humans, unchanged erdafitinib was the major circulating entity. O-demethylation of erdafitinib was the major metabolic pathway in humans and animals.