PBPK modeling to predict chemical distribution in brain and adipose tissues
PBPK modeling is used to facilitate decision-making in drug discovery and Risk Assessment. PBPK models are based on various assumptions and simplifications to make them computationally tractable. Most existing high-throughput, open-source PBPK models predict chemical concentrations in major body compartments such as the liver, kidney, and gut. However, estimates for additional organs require specialized models. As an example, for neurotoxicity evaluations, chemical concentrations in the brain depend upon the activity of the blood-brain barrier. Incorporating the blood-brain barrier in a PBPK model and evaluating whether a chemical can cross this barrier is an important step in assessing the potential neurotoxicity of the chemical. Another limitation of existing open-source PBPK models is that they often do not include an explicit adipose tissue compartment. Adipose tissue plays a critical role in toxicokinetics by acting as a storage compartment for lipophilic chemicals and a source of continuous internal exposure as the chemical is released.
To better estimate chemical concentrations in these two toxicologically relevant compartments, NIEHS and EPA scientists and collaborators added brain and adipose tissue compartments to the existing generic PBPK model from EPA’s httk R package (v2.2.2). Concentration–time profiles generated by the model for both hydrophilic and lipophilic chemicals were compared with in vivo data and also with predictions from commercial models. The alignment between the model's predictions against predictions from both commercial models and experimental data indicated that the PBPK model is robust and may be applicable to various aspects of drug development. The project is described in an abstract (Unnikrishnan et al.) accepted for a poster presentation at the 2024 annual meeting of the Society of Toxicology.