Effect of autoinduction and food on the pharmacokinetics of furmonertinib and its active metabolite characterized by a population pharmacokinetic model

doi:10.1038/s41401-021-00798-y

	Effect of autoinduction and food on the pharmacokinetics of furmonertinib and its active metabolite characterized by a population pharmacokinetic model
	Zou, Hui-xi 2; Zhang, Yu-feng 2; Zhong, Da-fang 1; Jiang, Yong 3; Liu, Fei 3; Zhao, Qian-yu 3; Zuo, Zhong 2; Zhang, Yi-fan 1; Yan, Xiao-yu 2
刊名	ACTA PHARMACOLOGICA SINICA
	2021-11-17
页码	10
关键词	furmonertinib autoinduction food effect alkaline phosphatase body weight pharmacokinetics modeling and simulation NSCLC
ISSN号	1671-4083
DOI	10.1038/s41401-021-00798-y
通讯作者	Zhang, Yi-fan(yfzhang@simm.ac.cn) ; Yan, Xiao-yu(xiaoyuyan@cuhk.edu.hk)
英文摘要	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.
资助项目	National Natural Science Foundation of China[81521005] ; School of Pharmacy, the Chinese University of Hong Kong
WOS关键词	CELL LUNG-CANCER ; GROWTH-FACTOR RECEPTOR ; EGFR MUTATION ; INCORPORATING AUTOINDUCTION ; OPEN-LABEL ; CHEMOTHERAPY ; THERAPY ; AST2818 ; PHASE-3 ; TIME
WOS研究方向	Chemistry ; Pharmacology & Pharmacy
语种	英语
出版者	NATURE PUBL GROUP
WOS记录号	WOS:000719724100001
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/298955]
专题	中国科学院上海药物研究所
通讯作者	Zhang, Yi-fan; Yan, Xiao-yu
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 2.Chinese Univ Hong Kong, Fac Med, Sch Pharm, Hong Kong, Peoples R China 3.Shanghai Allist Pharmaceut Technol Co Ltd, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Zou, Hui-xi,Zhang, Yu-feng,Zhong, Da-fang,et al. Effect of autoinduction and food on the pharmacokinetics of furmonertinib and its active metabolite characterized by a population pharmacokinetic model[J]. ACTA PHARMACOLOGICA SINICA,2021:10.
APA	Zou, Hui-xi.,Zhang, Yu-feng.,Zhong, Da-fang.,Jiang, Yong.,Liu, Fei.,...&Yan, Xiao-yu.(2021).Effect of autoinduction and food on the pharmacokinetics of furmonertinib and its active metabolite characterized by a population pharmacokinetic model.ACTA PHARMACOLOGICA SINICA,10.
MLA	Zou, Hui-xi,et al."Effect of autoinduction and food on the pharmacokinetics of furmonertinib and its active metabolite characterized by a population pharmacokinetic model".ACTA PHARMACOLOGICA SINICA (2021):10.