Enterohepatic Circulation Effect in Physiologically Based Pharmacokinetic Models: The Sorafenib Case

Sorafenib was recently approved by both the FDA and EMA for the treatment, of unresectable hepatocellular carcinoma (HCC), renal cell carcinoma (RCC), and thyroid cancer (DTC). This paper proposes a physiologically based model to describe its pharmacokinetic properties. Special attention is devoted to the enterohepatic circulation, which causes the characteristic double-peak in the drug's concentration-time curves. This physiologically based pharmacokinetic (PBPK) model has a structure suitable for different mammals. The paper focuses on the anatomy and physiology of mice aiming to develop a physiologically consistent model to produce accurate simulation of sorafenib pharmacokinetics, in agreement with literature data. The in silico description of sorafenib pharmacokinetics allows understanding further its properties, by complementing the experimental data with-numerical simulations based on a mechanistic approach. Modeling and simulation is a rapidly growing branch of quantitative systems pharmacology and supports new drug development by shortening analysis time, reducing costs, and delivering reliable pharmacokinetic knowledge.