Applied Concepts in PBPK Modeling: How to Build a PBPK/PD Model

Abstract

The aim of this tutorial is to introduce the fundamental concepts of physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) modeling with a special focus on their practical implementation in a typical PBPK model building workflow. To illustrate basic steps in PBPK model building, a PBPK model for ciprofloxacin will be constructed and coupled to a pharmacodynamic model to simulate the antibacterial activity of ciprofloxacin treatment.

Figure 1

(a) Representation of the generic structure of a whole‐body PBPK model. (b) Hierarchical representation of the main physiological and drug parameters in a PBPK model. (c) Simulation of drug concentrations in different tissues using different distribution models for theophylline. This illustrates the impact of the choice of the distribution model on the simulated tissue concentration profiles even though corresponding plasma concentrations are very similar. (d) Example of relative gene expression data for a group of enzymes (in healthy and cancer patients), receptors, and transporters. Gene expression is represented as relative value obtained through normalization to the tissue or organ with the highest expression.

Figure 2

Representation of the general building blocks which can be part of a PBPK model. Some components may be optional depending on the model considered.

Figure 3

Schematic representation of the most common applications of PBPK modeling.

Figure 4

Flowchart illustrating the steps usually used in PBPK model building.

Figure 5

(a) PBPK simulations for 200 mg CIP (i.v.).100 (b) PBPK simulation for 750 mg CIP (p.o.).100 (c) PBPK simulation for 500 mg b.i.d. (p.o.).18 (d) PBPK simulation for 1,000 mg q.d. (p.o.).18 (e) PD simulations with an adaptive Emax model that describes time‐kill profiles of E. coli (11775) in the context of various in vitro doses of CIP.18 (f) PBPK/PD simulations. q.d., once‐a‐day dosing; b.i.d., twice‐a‐day dosing.