Physiological Pharmacokinetic Pharmacodynamic Model And Its Applications

Pharmacokinetic model (PK model) is important in pharmacology, applied widely in drug research, development and use. Its physiologicalizing process was reviewed. A human propofol physiologically based pharmacokinetic/pharmacodynamic model (PBPK/PD model) was developed, analyzed and applied.In the review part, the physiologicalizing process of PK model was described, indicating that PBPK/PD model was the developing direction. A human propofol vascular-effect PBPK/PD model was proposed for the limitations of current propofol model.The hybrid modeling was used to make the model complexity moderate. The most of model parameters were measured experimentally or real physiological parameters. The BIS was contained in the model to describe the depth of anaesthesia (DOA). The total model was validated, for simulated results fitting the experiment results well. In model structural analysis, BIS was used to compare the influence of each part of the model to whole model. In model sensitivity analysis, the aortic plasma concentration was chosen to analyze model sensitivity to variance of model parameters.At last, the applications of this model were studied. The limitations were analyzed for TCIs based on traditional compartmental pharmacokinetic model. Three examples were used to illustrate the improved performance of TCIs based on PBPK/PD model. In inter-species extrapolation, a simple method was used to scale the pharmacokinetics form human to sheep and rats, and the results showed that predicted concentrations can represent measured concentrations basically.