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

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.

A workflow to build PBTK models for novel species

“…This implies in particular the application of best practice standards for model development and model qualification which are largely supported by full documentation and accessibility of the free and open PBPK software PK-Sim from the OSP software suite (OSP: open system pharmacology, https://www.open-systems-pharmacology.org ). In that sense, the previously published rabbit PBPK model (Mavroudis et al 2018 ) can be seen as a blueprint of our concept since it fulfils all requirements in terms of accessibility, reproducibility and qualification. Of note, the workflow applied is independent of the specific PBTK software used, but represents rather a generic concept of broad applicability for the identification of key model parameters, which can then be used to efficiently build PBTK models for novel species.…”

“…In contrast, the term “PBTK model” describes the full PBTK model including administration of a substance. Available and validated mammalian species models include human (Kuepfer et al 2016 ; Willmann et al 2003a ), monkey (Willmann et al 2007 ), minipig, dog (Willmann et al 2010 ), mouse (Schenk et al 2017 ; Thiel et al 2015 ), rat (Willmann et al 2003b ), and a recently developed rabbit model (Mavroudis et al 2018 ). For a broader applicability of PBTK models, it would clearly be desirable to have models for more species, e.g.…”

“…adopting the values from other mammalian species or calculating the value by means of extrapolation to limit the overall effort necessary. This approach was successfully taken for the parameterisation of the rabbit model (Mavroudis et al 2018 ).…”

ATLAS mPBPK: A MATLAB‐Based Tool for Modeling and Simulation of Minimal Physiologically‐Based Pharmacokinetic Models

“…Currently, mPBPK models can be developed through typical software platforms such as WinNonlin (Certara, Princeton, NJ, USA), NONMEM (ICON plc, Gaithersburg, MD, USA), ADAPT (BMSR Biomedical Simulations Resource, University of Southern California, Los Angeles, CA, USA), MATLAB (MathWorks, Natick, MA, USA), and many others as there is no specific computational tool needed for mPBPK modeling and simulation except for numerical integration. However, the critical steps of model development, verification, and validation such as sensitivity analysis (SA) of PK parameters are not part of the software design, and most of the time are cumbersome to perform . In this tutorial, we describe a new MATLAB‐based tool for the modeling and simulation of mPBPK models (ATLAS mPBPK).…”

“…However, the critical steps of model development, verification, and validation such as sensitivity analysis (SA) of PK parameters are not part of the software design, and most of the time are cumbersome to perform. [13][14][15][16] In this tutorial, we describe a new MATLAB-based tool for the modeling and simulation of mPBPK models (ATLAS mPBPK). This software offers a number of different predefined mPBPK models based on which the user can perform the following: (i) simulations, (ii) parameter optimization, and (iii) SA.…”