Pharmacokinetics and BTK occupancy prediction for ibrutinib and acalabrutinib based on PBPK-BK-TK Model

Aim To construct a PBPK-BK-TK mathematical model integrating physiologically-based pharmacokinetics(PBPK), binding kinetics(BK), and target kinetics(TK), to simulate the dynamic changes of blood concentration and target occupancy of Bruton' s tyrosine kinase(BTK)inhibitors ibrutinib and acalabrutinib, and to verify the predictive performance process of the model.MethodsThe absorption, distribution, metabolism and excretion of drugs in the gastrointestinal tract, liver, kidney and other tissues were described by differential equation modeling with the incorporation of drug-target binding and dissociation rate constants (kon, koff) and target protein turnover and degradation rate constants (kturnover, kdeg). Parameter sensitivity analysis and folding error were used to validate the model performance, and the prediction accuracy was assessed by comparing the measured data.ResultsThe model predicted both inhibitors well, with folding errors ranging from 1.02 to 1.34, all within reasonable limits, and the simulated dynamic curves were in good agreement with literature measurements.ConclusionsThe establishment of the PBPK-BK-TK model provides an effective mathematical modeling tool for drug dose optimization. Subsequent experimental refinement of the model parameters and integration of physiological data from individualized populations can further improve the predictive performance of the model and provide reference for new drug development and clinical use.