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.