Metabolism and disposition in rats, dogs, and humans of erdafitinib, an orally administered potent pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor.
Xenobiotica
; 51(2): 177-193, 2021 Feb.
Article
em En
| MEDLINE
| ID: mdl-32902324
ABSTRACT
This article describes in vivo biotransformation and disposition of erdafitinib following single oral dose of 3H-erdafitinib and 14C-erdafitinib to intact and bile duct-cannulated (BC) rats (4 mg/kg), 3H-erdafitinib to intact dogs (0.25 mg/kg), and 14C-erdafitinib to humans (12 mg; NCT02692677). Peak plasma concentrations of total radioactivity were achieved rapidly (Tmax 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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Pirazóis
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Quinoxalinas
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Receptores de Fatores de Crescimento de Fibroblastos
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Inibidores de Proteínas Quinases
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Humans
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Male
Idioma:
En
Revista:
Xenobiotica
Ano de publicação:
2021
Tipo de documento:
Article