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

• Published in: Toxicology and applied pharmacology 2022-04, Vol.440, p.115922-115922, Article 115922
• Main Authors: Hoer, Daniel, Barton, Hugh A., Paini, Alicia, Bartels, Michael, Ingle, Brandall, Domoradzki, Jeanne, Fisher, Jeffrey, Embry, Michelle, Villanueva, Philip, Miller, David, Nguyen, James, Zhang, Qiang, Edwards, Stephen W., Tan, Yu-Mei
• Format: Article
• Language: English
• Subjects: Animal Study Design; Animals; Internal Concentrations; Models, Biological; Nonlinear Pharmacokinetics; Physiologically Based Pharmacokinetic (PBPK); Rats; Saturation of Absorption; Saturation of Clearance
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2022.115922

Although external concentrations are more readily quantified and often used as the metric for regulating and mitigating exposures to environmental chemicals, the toxicological response to an environmental chemical is more directly related to its internal concentrations than the external concentration. The processes of absorption, distribution, metabolism, and excretion (ADME) determine the quantitative relationship between the external and internal concentrations, and these processes are often susceptible to saturation at high concentrations, which can lead to nonlinear changes in internal concentrations that deviate from proportionality. Using generic physiologically-based pharmacokinetic (PBPK) models, we explored how saturable absorption or clearance influence the shape of the internal to external concentration (IEC) relationship. We used the models for hypothetical chemicals to show how differences in kinetic parameters can impact the shape of an IEC relationship; and models for styrene and caffeine 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 to demonstrate how a PBPK modeling approach can be an alternative to common statistical methods for analyzing dose proportionality. A PBPK modeling approach can be a valuable tool used in the early stages of a chemical safety assessment program to optimize the design of longer-term animal toxicity studies or to interpret study results. •Saturable kinetics can lead to nonlinear internal to external concentration curve.•Improved understanding of kinetics support better study design and interpretation.•A PBPK model can provide insight into the impact of saturable kinetics.•Case studies demonstrate the use of a PBPK model to analyze dose proportionality.