PK/PBPK models

Physiologically based pharmacokinetic (PBPK) modeling aims to link an external exposure to an internal dosimetry (e.g. concentration in blood, urine, or in tissues) by describing the Absorption, Disposition, Metabolism and Elimination (ADME) processes that undergoes a substance in living organisms. Those models take into account the physiology, the anatomy of individuals, and the biochemistry of the compounds. A PBPK model subdivides the body in compartments representing organs connected through a fluid, usually blood. Model parameters correspond to physiological and biochemical entities specific to the body and compounds, such as organ volumes, tissue blood flows, affinities of the compounds for the tissues, or the metabolic clearance.

The advantages of the mechanistic basis of PBPK models approach are (i) the integration of diverse information from different sources (e.g. in vitro or in vivo experiments, structure-activity models); (ii) the extrapolation capability to different species (e.g. laboratory animals to human populations), exposure scenarios (e.g. various exposure or dosing schemes) or physiological conditions (e.g. elderly, pregnancy); and (iii) the fact that they are well suited to be coupled with other model type (exposure model, DEB model).

PBPK models can be applied in two different steps of the risk assessment framework. First, these models can be used to better characterize the relationship between the exposure dose and the adverse effects by modeling the internal exposure in the target tissues (i.e. where the toxic effects arise). Secondly, PBPK models can be used in the exposure assessment to estimate the external exposure using human biomonitoring data, like the concentrations of chemicals in blood or urine. These predictions can then be compared to existing exposure guidance or reference values such as tolerable daily intakes.

For environmental risk assessment, we develop PBPK and semi-physiologically based models for fish and for molluscs. Semi-physiologically based models refer to simplified models that do not rely entirely on physiological processes. In addition, to better explain, predict, or extrapolate to humans the developmental toxicity effects of chemicals to zebrafish embryo, we developed a physiologically-based pharmacokinetic (PBPK) model able to predict organ concentrations of neutral or ionizable chemicals, up to 120 hours post fertilization.

We are also researching models of in vitro kinetics.

Software

See our Software page for models and tools developed.

Briefly, we developed a generic PBPK model (on Zenodo at DOI 10.5281/zenodo.3553689) which is included in the MCRA (Monte Carlo Risk Assessment) toolbox, within the Euromix project.

Our PBPK models also feature in the Merlin Expo software for assessing the fate of chemicals in the human body (see documentation).

Key publications

- Bois F., Jamei M., Clewell H.J., 2010, PBPK modelling of inter-individual variability in the pharmacokinetics of environmental chemicals, Toxicology, 278:256-267.
- Coecke S., Pelkonen O., Batista Leite S., Bernauer U., Bessems J., Bois F., Gundert-Remy U., Loizou G., Testai E., Zaldívar J.M., 2013, Toxicokinetics as a key to the integrated toxicity risk assessment based primarily on non-animal approaches, Toxicology in Vitro, 27:1570-1577, doi: 10.1016/j.tiv.2012.06.012.
- Bois FY, Brochot C. Modeling Pharmacokinetics. Methods Mol Biol. 2016;1425:37-62.
- Grech A, Brochot C, Dorne JL, Quignot N, Bois FY, Beaudouin R. Toxicokinetic models and related tools in environmental risk assessment of chemicals. Sci Total Environ. Volume 578, 1 February 2017, Pages 1–15.

S Siméon, K Brotzmann, C Fisher, I Gardner, S Silvester, R Maclennan, P Walker, T Braunbeck and FY Bois. Development of a generic zebrafish embryo PBPK model and application to the developmental toxicity assessment of valproic acid. in press, Reproductive Toxicology

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