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

Abstract

(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.