Metabolic disposition of the EGFR covalent inhibitor furmonertinib in humans  

作　　者：Jian Meng Hua Zhang Jing-jing Bao Zhen-dong Chen Xiao-yun Liu Yi-fan Zhang Yong Jiang Li-yan Miao Da-fang Zhong 

机构地区：[1]State Key Laboratory of Drug Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201210,China [2]The First Affiliated Hospital of Soochow University,Suzhou 215006,China [3]Shanghai Allist Pharmaceuticals Inc.,Shanghai,201203,China

出　　处：《Acta Pharmacologica Sinica》2022年第2期494-503,共10页中国药理学报（英文版）

基　　金：This article was supported by the Strategic Priority Research Program of the Chinese Academy of Sciences(No.XDA12050306);the National Natural Science Foundation of China(No.81521005).

摘　　要：Furmonertinib was designed for the treatment of non-small cell lung cancer (NSCLC) patients with EGFR T790M mutation. In this study, we investigated the metabolic disposition and mass balance in humans and tissue distribution in rats. After a single oral administration of 97.9 μCi/81.5 mg [14C]-furmonertinib mesylate to six healthy male volunteers, the absorption process of furmonertinib was fast with a tmax of total plasma radioactivity at 0.75 h. Afterward, furmonertinib was extensively metabolized, with the parent drug and active metabolite AST5902 accounting for 1.68% and 0.97% of total radioactivity in plasma. The terminal t1/2 of total radioactivity in plasma was as long as 333 h, suggesting that the covalent binding of drug-related substances to plasma proteins was irreversible to a great extent. The most abundant metabolites identified in feces were desmethyl metabolite (AST5902), cysteine conjugate (M19), and parent drug (M0), which accounted for 6.28%, 5.52%, and 1.38% of the dose, respectively. After intragastric administration of 124 μCi/9.93 mg/kg [14C]-furmonertinib to rats, drug-related substances were widely and rapidly distributed in tissues within 4 h. The concentration of total radioactivity in the lung was 100-fold higher than that in rat plasma, which could be beneficial to the treatment of lung cancer. Mass balance in humans was achieved with 77.8% of the administered dose recovered in excretions within 35 days after administration, including 6.63% and 71.2% in urine and feces, respectively. In conclusion, [14C]-furmonertinib is completely absorbed and rapidly distributed into lung tissue, extensively metabolized in humans, presented mostly as covalent conjugates in plasma, and slowly eliminated mostly via fecal route.

关 键 词：METABOLISM mass balance distribution covalent binding furmonertinib 

分 类 号：R96[医药卫生—药理学]