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Development and Verification of a Physiologically Based Pharmacokinetic Model of Furmonertinib and Its Main Metabolite for Drug-Drug Interaction Predictions

文献类型：期刊论文

作者Wu, Yali3,4,5; Loer, Helena Leonie Hanae2; Zhang, Yifan5; Zhong, Dafang5; Jiang, Yong1; Hu, Jie1; Fuhr, Uwe3,4; Lehr, Thorsten2; Diao, Xingxing5
刊名CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY
出版日期2025-07-01
卷号14期号:7页码:1273-1284
ISSN号2163-8306
DOI10.1002/psp4.70052
通讯作者Fuhr, Uwe(uwe.fuhr@uk-koeln.de) ; Lehr, Thorsten(thorsten.lehr@mx.uni-saarland.de) ; Diao, Xingxing(xxdiao@simm.ac.cn)
英文摘要Furmonertinib demonstrated potent efficacy as a newly developed tyrosine kinase inhibitor for the treatment of patients with epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer. In vitro research showed that furmonertinib is metabolized to its active metabolite AST5902 via the cytochrome P450 (CYP) enzyme CYP3A4. Furmonertinib is a strong CYP3A4 inducer, while the metabolite is a weaker CYP3A4 inducer. In clinical studies, nonlinear pharmacokinetics were observed during chronic dosing. The apparent clearance showed time- and dose-dependent increases. In this evaluation, a combination of in vitro data using radiolabeled compounds, clinical pharmacokinetic data, and drug-drug interaction (DDI) data of furmonertinib in oncology patients and/or in healthy subjects was used to develop a physiologically based pharmacokinetic (PBPK) model. The model was built in PK-Sim Version 11 using a total of 44 concentration-time profiles of furmonertinib and its metabolite AST5902. Suitability of the predictive model performance was demonstrated by both goodness-of-fit plots and statistical evaluation. The model predicted the observed monotherapy concentration profiles of furmonertinib well, with 32/32 predicted AUClast (area under the curve until the last concentration measurement) values and 32/32 maximum plasma concentration (Cmax) ratios being within twofold of the respective observed values. In addition, 8/8 predicted DDI AUClast and Cmax ratios with furmonertinib as a victim of CYP3A4 inhibition or induction were within twofold of their respective observed values. Potential applications of the final model include the prediction of DDIs for chronic administration of CYP3A4 perpetrators along with furmonertinib, considering auto-induction of furmonertinib and its metabolite AST5902.
WOS关键词TYROSINE KINASE INHIBITORS ; COVALENT BINDING ; HUMAN CYP2C9 ; RECEPTOR ; CANCER ; EXPRESSION ; MUTATIONS
资助项目National Key R&D Program of China
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001509761500001
出版者WILEY
源URL[http://119.78.100.183/handle/2S10ELR8/318377]  
专题中国科学院上海药物研究所
通讯作者Fuhr, Uwe; Lehr, Thorsten; Diao, Xingxing
作者单位1.Shanghai Allist Pharmaceut Co Ltd, Shanghai, Peoples R China
2.Saarland Univ, Clin Pharm, Saarbrucken, Germany
3.Univ Cologne, Univ Hosp Cologne, Cologne, Germany
4.Univ Cologne, Fac Med, Ctr Pharmacol, Dept Pharmacol 1,Clin Pharmacol, Cologne, Germany
5.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai, Peoples R China
推荐引用方式
GB/T 7714		 Wu, Yali,Loer, Helena Leonie Hanae,Zhang, Yifan,et al. Development and Verification of a Physiologically Based Pharmacokinetic Model of Furmonertinib and Its Main Metabolite for Drug-Drug Interaction Predictions[J]. CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY,2025,14(7):1273-1284.
APA Wu, Yali.,Loer, Helena Leonie Hanae.,Zhang, Yifan.,Zhong, Dafang.,Jiang, Yong.,...&Diao, Xingxing.(2025).Development and Verification of a Physiologically Based Pharmacokinetic Model of Furmonertinib and Its Main Metabolite for Drug-Drug Interaction Predictions.CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY,14(7),1273-1284.
MLA Wu, Yali,et al."Development and Verification of a Physiologically Based Pharmacokinetic Model of Furmonertinib and Its Main Metabolite for Drug-Drug Interaction Predictions".CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY 14.7(2025):1273-1284.

入库方式： OAI收割

来源：上海药物研究所

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