Physiologically Based Pharmacokinetic Modeling: Methodology, Applications, and Limitations with a Focus on Its Role in Pediatric Drug Development
Figure 1
The concept for building a PBPK model modified according to Willmann et al. [13]. (a) Organisms (e.g., humans of different ages or populations) are the basis for the model. (b) The organism is divided into a number of compartments, each representing a single organ. To describe the distribution of compounds in the body, the organs are connected via their arteries and veins to the arterial and venous blood pool. Intercompartmental mass transport occurs via organ-specific blood flow rates. The organs are mathematically connected. (c) Division of each organ into three subcompartments representing the vascular space with blood cells and the interstitial and cellular space. The interstitial space is assumed to be in direct contact with the plasma. The exchange of substances between the cellular and interstitial compartment can occur by permeation across the membranes via passive diffusion as well as active influx and efflux transport processes by saturable Michaelis-Menten (MM) kinetics with and as parameters. Metabolism of substances (Meta1 and Meta2) occurs via active enzymes (MM kinetics). Finally, the model consists of a large number of coupled differential equations. (d) Output of the model : concentration time curves for the substances shown are simulated and observed ciprofloxacin concentrations in various organs after ciprofloxacin 5 mg/kg was intravenously applied to a rat.
