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Prediction for Plasma Trough Concentration and Optimal Dosing of Imatinib under Multiple Clinical Situations Using Physiologically Based Pharmacokinetic Modeling

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机构： [1]Department of Medical Oncology, Bethune International Peace Hospital, Shijiazhuang 050082, China. [2]Zhongcai Health (Beijing) Biological Technology Development Co., Ltd., Beijing 101500, China. [3]Department of Clinical Pharmacy, Bethune International Peace Hospital, Shijiazhuang 050082, China. [4]Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610041, China. [5]Institute of Chinese Material Medica China Academy of Chinese Medical Sciences, Beijing 100700, China.

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(1) Purpose: This study aimed to develop a physiologically based pharmacokinetic (PBPK) model to predict the trough concentration (C trough) of imatinib (IMA) at steady state in patients and to explore the role of free concentration (f up), α1-acid glycoprotein (AGP) level, and organic cation transporter 1 (OCT1) activity/expression in clinical efficacy. (2) Methods: The population PBPK model was built using physicochemical and biochemical properties, metabolizing and transporting kinetics, tissue distribution, and human physiological parameters. (3) Results: The PBPK model successfully predicted the C trough of IMA administered alone in chronic phase (CP) and accelerated phase (AP) patients, the C trough of IMA co-administered with six modulators, and C trough in CP patients with hepatic impairment. Most of the ratios between predicted and observed data are within 0.70-1.30. Additionally, the recommendations for dosing adjustments for IMA have been given under multiple clinical uses. The sensitivity analysis showed that exploring the f up and AGP level had a significant influence on the plasma C trough of IMA. Meanwhile, the simulations also revealed that OCT1 activity and expression had a significant impact on the intracellular C trough of IMA. (4) Conclusion: The current PBPK model can accurately predict the IMA C trough and provide appropriate dosing adjustment recommendations in a variety of clinical situations.© 2023 The Authors. Published by American Chemical Society.

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出版当年[2023]版：

大类 | 3 区化学

小类 | 3 区化学：综合

最新[2023]版：

大类 | 3 区化学

小类 | 3 区化学：综合

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出版当年[2023]版：

Q2 CHEMISTRY, MULTIDISCIPLINARY

最新[2023]版：

Q2 CHEMISTRY, MULTIDISCIPLINARY

影响因子： 3.7 最新[2023版] 4 最新五年平均 3.7 出版当年[2023版] 4 出版当年五年平均 4.1 出版前一年[2022版]

第一作者：

第一作者机构： [1]Department of Medical Oncology, Bethune International Peace Hospital, Shijiazhuang 050082, China.

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通讯作者：

通讯机构： [4]Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610041, China. [5]Institute of Chinese Material Medica China Academy of Chinese Medical Sciences, Beijing 100700, China. [*1]Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610041, China [*2]Institute of Chinese Material Medica China Academy of Chinese Medical Sciences, Beijing 100700, China

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