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

(1) : This study aimed to develop a physiologically based pharmacokinetic (PBPK) model to predict the trough concentration ( ) of imatinib (IMA) at steady state in patients and to explore the role of free concentration ( ), α1-acid glycoprotein (AGP) level, and organic cation transporter 1 (OCT1) activity/expression in clinical efficacy. (2) : The population PBPK model was built using physicochemical and biochemical properties, metabolizing and transporting kinetics, tissue distribution, and human physiological parameters. (3) : The PBPK model successfully predicted the of IMA administered alone in chronic phase (CP) and accelerated phase (AP) patients, the of IMA co-administered with six modulators, and 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 and AGP level had a significant influence on the plasma of IMA. Meanwhile, the simulations also revealed that OCT1 activity and expression had a significant impact on the intracellular of IMA. (4) : The current PBPK model can accurately predict the IMA and provide appropriate dosing adjustment recommendations in a variety of clinical situations.