Abstract

1. 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).

2. Peak plasma concentrations of total radioactivity were achieved rapidly (T _max: 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%).

3. 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.

4. In humans, unchanged erdafitinib was the major circulating entity. O-demethylation of erdafitinib was the major metabolic pathway in humans and animals.

摘要

1. 本文描述了完整口服和胆管插管（BC）大鼠（4 mg / kg），完整犬只³ H-erdafitinib口服一次³ H-erdafitinib和¹⁴ C-erdafitinib（3 mg / kg），³ H-erdafitinib（单次口服）后，erdafitinib的体内生物转化和处置0.25 mg / kg）和¹⁴ C-erdafitinib（12 mg; NCT02692677）。

2. 血浆总放射性的峰值浓度迅速达到（T _max：动物，1 h；人类，2–3 h）。与动物（大鼠：91–98％，48小时；狗：81％，72小时）相比，人类（87％，384小时）的药物来源的放射性的恢复明显较慢。在完整大鼠（95％），狗（76％）和人类（69％）中，粪便是消除的主要途径。和BC大鼠胆汁（48％）。与人类（19％）相比，动物（2–12％）对肾脏的放射性消除相对较低。

3. 相对于动物，未改变的erdafitinib是人类排泄物中的主要成分（粪便占17％；尿占11％）。M6（O-去甲基）是人类（24％）和大鼠（完整，46％； BC，11％）的主要粪便代谢产物，而M2（M6的O-葡萄糖醛酸）是大鼠中主要的胆汁代谢产物（14％） ）。在犬中，除M6外，粪便中的放射性剂量主要由多种次要代谢物组成。

4. 在人类中，未改变的erdafitinib是主要的循环实体。厄达菲替尼的O-去甲基化是人类和动物体内的主要代谢途径。