A workflow to build PBTK models for novel species

Arch Toxicol. 2020 Nov;94(11):3847-3860. doi: 10.1007/s00204-020-02922-z. Epub 2020 Oct 9.

Abstract

Physiology-based pharmacokinetic and toxicokinetic (PBPK/TK) models allow us to simulate the concentration of xenobiotica in the plasma and different tissues of an organism. PBPK/TK models are therefore routinely used in many fields of life sciences to simulate the physiological concentration of exogenous compounds in plasma and tissues. The application of PBTK models in ecotoxicology, however, is currently hampered by the limited availability of models for focal species. Here, we present a best practice workflow that describes how to build PBTK models for novel species. To this end, we extrapolated eight previously established rabbit models for several drugs to six additional mammalian species (human, beagle, rat, monkey, mouse, and minipig). We used established PBTK models for these species to account for the species-specific physiology. The parameter sensitivity in the resulting 56 PBTK models was systematically assessed to rank the relevance of the parameters on overall model performance. Interestingly, more than 80% of the 609 considered model parameters showed a negligible sensitivity throughout all models. Only approximately 5% of all parameters had a high sensitivity in at least one of the PBTK models. This approach allowed us to rank the relevance of the various parameters on overall model performance. We used this information to formulate a best practice guideline for the efficient development of PBTK models for novel animal species. We believe that the workflow proposed in this study will significantly support the development of PBTK models for new animal species in the future.

Keywords: Best practice workflow; Cross-species extrapolation; OSP; PBPK; PBTK; Physiologically-based pharmacokinetic modelling.

MeSH terms

  • Animals
  • Dogs
  • Drug Evaluation / methods*
  • Haplorhini
  • Mice
  • Models, Biological*
  • Pharmacokinetics*
  • Practice Guidelines as Topic*
  • Rabbits
  • Rats
  • Risk Assessment
  • Species Specificity
  • Swine
  • Workflow
  • Xenobiotics

Substances

  • Xenobiotics