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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Pharmacol. | doi: 10.3389/fphar.2019.01394

Development, testing, parameterisation and calibration of a human PBPK model for the plasticiser, Hexamoll® DINCH using in silico, in vitro and human biomonitoring data

 George D. Loizou1*, Craig Sams1 and  Kevin McNally1
  • 1Health and Safety Executive, United Kingdom

A physiologically based pharmacokinetic model for Hexamoll® DINCH (diisononyl-cyclohexane-1, 2-dicarboxylate) was developed to interpret the biokinetics in humans after single oral doses. The model was parameterised with in vitro and in silico derived parameters and uncertainty and sensitivity analysis was used during the model development process to assess structure, biological plausibility and behaviour prior to simulation and analysis of human biological monitoring (HBM) data. The model provided good simulations of the urinary excretion (Curine) of two metabolites; cyclohexane-1,2-dicarboxylic acid mono hydroxyisononyl ester (OH-MINCH) and cyclohexane-1, 2-dicarboxylic acid mono carboxyisononyl ester (cx-MINCH) from the biotransformation of mono-isononyl-cyclohexane-1, 2-dicarboxylate (MINCH), the monoester metabolite of DINCH. However, good simulations could be obtained, with and without, a lymphatic compartment. Selection of an appropriate model structure was informed by sensitivity analysis which could identify and quantify the contribution to variability in Curine by parameters, such as, the fraction of oral dose that directly entered the lymphatic compartment and therefore by-passed the liver and the fraction of MINCH bio-transformed to cx-MINCH and OH-MINCH. By constraining these parameters within biologically plausible limits the presence of a lymphatic compartment was deemed an important component of model structure. Furthermore, the use of sensitivity analysis is important in the evaluation of uncertainty around in silico derived parameters. By quantifying their impact on model output sufficient confidence in the use of a model should be afforded. This type of approach could expand the use of PBPK models since parameterisation with in silico techniques allows for rapid model development. This in turn could assist in reducing the use of animals in toxicological evaluations by enhancing the utility of “read across” techniques.

Keywords: plasticiser, Hexamoll® DINCH, PBPK, in silico, in vitro, biomonitoring, Bayesian, Markov chain Monte Carlo, Reverse dosimetry

Received: 17 May 2019; Accepted: 31 Oct 2019.

Copyright: © 2019 Loizou, Sams and McNally. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. George D. Loizou, Health and Safety Executive, Bootle, United Kingdom, george.loizou@hse.gov.uk