Furmonertinib(AST2818)is a novel third-generation irreversible EGFR TKI and recently has been approved in China for the treatment of non-small cell lung cancer(NSCLC)with EGFR-sensitizing and T790M resistance mutations.In the current study,we developed a semi-mechanistic population pharmacokinetic model to characterize the nonstationary pharmacokinetics(PK)of the furmonertinib and its active metabolite AST5902 simultaneously.The PK data of furmonertinib and AST5902 were obtained from 38 NSCLC patients and 16 healthy volunteers receiving 20-240 mg furmonertinib in three clinical trials.A nonlinear mixed-effects modeling approach was used to describe the PK data.The absorption process of furmonertinib was described by a transit compartment model.The disposition of both furmonertinib and AST5902 was described by a two-compartment model.An indirect response model accounted for the autoinduction of furmonertinib metabolism mediated by CYP3A4.The model-based simulation suggested that furmonertinib clearance was increased in one cycle of treatment(orally once daily for 21 days)compared to baseline,ranging from 1.1 to 1.8 fold corresponding to the dose range of 20-240 mg.The concentration of furmonertinib was decreased over time whereas that of AST5902 was increased.Interestingly,the concentration of the total active compounds(furmonertinib and AST5902)appeared to be stable.The food intake,serum alkaline phosphatase and body weight were identified as statistically significant covariates.The mechanism of food effect on PK was investigated,where the food intake might increase the bioavailability of furmonertinib via increasing the splanchnic blood flow.Overall,a population PK model was successfully developed to characterize the nonstationary PK of furmonertinib and AST5902 simultaneously.The concentrations of total active compounds were less affected by the autoinduction of furmonertinib metabolism.

Hui-xi Zou;Yu-feng Zhang;Da-fang Zhong;Yong Jiang;Fei Liu;Qian-yu Zhao;Zhong Zuo;Yi-fan Zhang;Xiao-yu Yan

School of Pharmacy,Faculty of Medicine,The Chinese University of Hong Kong,Hong Kong,China;State Key Laboratory of Drug Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203,China;Shanghai Allist Pharmaceutical Technology Co.,Ltd.,Shanghai 201203,China

中国药理学报（英文版）

[1]Hui-xi Zou;Yu-feng Zhang;Da-fang Zhong;Yong Jiang;Fei Liu;Qian-yu Zhao;Zhong Zuo;Yi-fan Zhang;Xiao-yu Yan-.Effect of autoinduction and food on the pharmacokinetics of furmonertinib and its active metabolite characterized by a population pharmacokinetic model)[J].中国药理学报（英文版）,2022(07):1865-1874

autoinduction,furmonertinib,Furmonertinib,AST2818,AST5902

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