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

[Image: see text] (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.