Background: Accompanied by significant improvements of modeling techniques and computational
methods in medical sciences, the last thirty years saw the flourishing of pharmacokinetic models
for applications in the pharmacometric field. In particular, physiologically based pharmacokinetic
(PBPK) models, grounded on a mechanistic foundation, have been applied to explore a multiplicity of
aspects with possible applications in patient care and new drugs development, as in the case of siRNA
Method: This article summarizes the features we recently introduced in PBPK modeling within a threeyear
research project funded by Italian Research Ministry. Four major points are detailed: (i) the mathematical
formulation of the model, which allows modulating its complexity as a function of the administration
route and active principle; (ii) a dedicated parameter of the PBPK model quantifies the drugprotein
binding, which affects the active principle distribution; (iii) the gall bladder compartment and
the bile enterohepatic circulation process; (iv) the coupling of the pharmacokinetic and pharmacodynamic
models to produce an overall understanding of the drug effects on mammalian body.
Results: The proposed model is applied to two separate endovenous (remifentanil) and oral (sorafenib)
drug administrations. The resulting PBPK simulations are consistent with the literature experimental data.
Blood concentration predictability is confirmed in multiple reference subjects. Furthermore, in case
of sorafenib administration in mice, it is possible to evaluate the drug concentration in the liver and reproduce
the effects of the enterohepatic circulation. Finally, a preliminary application of the coupling of
the pharmacokinetic/pharmacodynamic models is presented and discussed.