Predicting nonlinear relationships between external and internal concentrations with physiologically based pharmacokinetic modeling

Generic physiologically-based pharmacokinetic (PBPK) models were used to explore how saturable absorption or clearance can influence the shape of the internal to external concentration (IEC) relationship. The models were used for hypothetical chemicals to show how differences in kinetic parameters can impact the shape of an IEC relationship; and the models for styrene and caffeine were used to explore how exposure route, frequency, and duration impact the IEC relationships in rat and human exposures. We also analyzed available plasma concentration data for 2,4-dichlorophenoxyacetic acid (data from Saghir et al. 2013; https://doi.org/10.1093/toxsci/kft212) to demonstrate how a PBPK modeling approach can be an alternative to common statistical methods for analyzing dose proportionality. These files contain the model code and utilized parameters for each of these case studies as well as a link to the publicly available dataset from Saghir et al. 2013 (https://doi.org/10.1093/toxsci/kft212). Citation information for this dataset can be found in Data.gov's References section.

[
  "020:00"
]

[
  "020:000"
]

[
  "https://dx.doi.org/10.1016/j.taap.2022.115922",
  "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10519136"
]