Development and validation of a physiology-based model for the prediction of pharmacokinetics/toxicokinetics in rabbits

PLoS One. 2018 Mar 21;13(3):e0194294. doi: 10.1371/journal.pone.0194294. eCollection 2018.

Abstract

The environmental fates of pharmaceuticals and the effects of crop protection products on non-target species are subjects that are undergoing intense review. Since measuring the concentrations and effects of xenobiotics on all affected species under all conceivable scenarios is not feasible, standard laboratory animals such as rabbits are tested, and the observed adverse effects are translated to focal species for environmental risk assessments. In that respect, mathematical modelling is becoming increasingly important for evaluating the consequences of pesticides in untested scenarios. In particular, physiologically based pharmacokinetic/toxicokinetic (PBPK/TK) modelling is a well-established methodology used to predict tissue concentrations based on the absorption, distribution, metabolism and excretion of drugs and toxicants. In the present work, a rabbit PBPK/TK model is developed and evaluated with data available from the literature. The model predictions include scenarios of both intravenous (i.v.) and oral (p.o.) administration of small and large compounds. The presented rabbit PBPK/TK model predicts the pharmacokinetics (Cmax, AUC) of the tested compounds with an average 1.7-fold error. This result indicates a good predictive capacity of the model, which enables its use for risk assessment modelling and simulations.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms
  • Animals
  • Area Under Curve
  • Computer Simulation
  • Inulin / pharmacokinetics
  • Inulin / toxicity
  • Models, Biological*
  • Pharmacokinetics*
  • Rabbits
  • Reproducibility of Results
  • Toxicokinetics*
  • Workflow

Substances

  • Inulin

Grants and funding

This study was funded by Bayer Technology Services GmbH and Bayer Crop Science AG. At the time of the study, all authors were employees of Bayer AG. Bayer AG provided support in the form of salaries for all authors but had no role in the study design, data collection and analysis, decision to publish and preparation of the manuscript. The specific roles of all authors are articulated in the ‘author contributions’ section.