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

  • Publication Date :
  • Publication Type : Journal Article
  • Author(s) : Hoer D, Barton HA, Paini A, Bartels M, Ingle B, Domoradzki J, Fisher J, Embry M, Villanueva P, Miller D, Nguyen J, Zhang Q, Edwards SW, Tan YM
  • Journal Name : Toxicology and Applied Pharmacology

A physiologically based pharmacokinetic (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.

This proof of principle study, involving multiple test cases, demonstrates that a PBPK model can be developed as a research tool to integrate available absorption, distribution, metabolism, and excretion (ADME) data from shorter-term in vivo studies or in vitro assays to simulate longer term exposure, which can inform dose selection, dose spacing, or sample collection intervals in future whole animal studies. A PBPK model can also be used to interpret toxicity testing results, generate hypotheses on potential modes of action, or identify early mechanistic biomarkers. These capabilities can potentially reduce animal use in longer-term studies, as well as improve our understanding of the study outcomes by providing insight into the internal to external concentration (IEC) relationship.

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