Physiologically based pharmacokinetic models: mathematical fundamentals and simulation implementations.

This review paper gives an overview of the building blocks of physiologically based pharmacokinetic (PBPK) models and their implementation using computer facilities. The approach focuses on the development of a PBPK model with the most important and appropriate limiting steps for the conditions and exposure scenarios under study. In this approach, the assumptions made in constructing the set of equations, as well as the fitting of variables to specific experimental results, need to be accounted for when making extrapolation to other conditions. A well-constructed PBPK model should account for all possible ranges of extrapolation from the development stages so that appropriate experimental studies and assumptions can be designed to handle the intended applications. Two common assumptions are revisited: the flow-limited assumption and the metabolic clearance using Michaelis-Menten kinetics assumption. Computer hardware and software requirements for implementing PBPK models are briefly reviewed.