A Systematic Review of Published Physiologically-based Kinetic Models and an Assessment of their Chemical Space Coverage

Abstract

Across multiple sectors, including food, cosmetics and pharmaceutical industries, there is a need to predict the potential effects of xenobiotics. These effects are determined by the intrinsic ability of the substance, or its derivatives, to interact with the biological system, and its concentration–time profile at the target site. Physiologically based kinetic (PBK) models can predict organ-level concentration–time profiles — however, the models are time and resource intensive to generate de novo. Read-across is an approach used to reduce or replace animal testing, wherein information from a data-rich chemical is used to make predictions for a data-poor chemical. The recent increase in published PBK models presents the opportunity to use a read-across approach for PBK modelling, that is, to use PBK model information from one chemical to inform the development or evaluation of a PBK model for a similar chemical. Essential to this process, is identifying the chemicals for which a PBK model already exists. Herein, the results of a systematic review of existing PBK models, compliant with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) format, are presented. Model information, including species, sex, life-stage, route of administration, software platform used and the availability of model equations, was captured for 7541 PBK models. Chemical information (identifiers and physico-chemical properties) has also been recorded for 1150 unique chemicals associated with these models. This PBK model data set has been made readily accessible, as a Microsoft Excel® spreadsheet, providing a valuable resource for those developing, using or evaluating PBK models in industry, academia and the regulatory sectors.

A permeability‐ and perfusion‐based PBPK model for improved prediction of concentration‐time profiles

“…After model development, a test set was used to evaluate the model. A review of PBPK models by Thompson et al 42 was used to select the test set. From this review, PBPK models published between 2018 and 2021 provided five drugs for which IV data and the required in vitro parameters were available.…”

Towards best use and regulatory acceptance of generic physiologically based kinetic (PBK) models for in vitro-to-in vivo extrapolation (IVIVE) in chemical risk assessment

“…However, this requires more initiatives for data sharing amongst different sectors. Along these lines, the European Partnership for Alternative Approaches to Animal Testing (EPAA) is currently working on assessing the chemical space coverage of existing PBK models (Thompson et al 2021) and determining methods to identify 'similar' chemicals in support of read across.…”

Generic solving of physiologically-based kinetic models in support of next generation risk assessment due to chemicals

“…Multi-compartment models reveal sometimes absolutely necessary, for example in finely deciphering the internal contamination routes of specific chemical compounds that cause damages to only target organs [7, 1, 13]. Additionally, PBK models can be of crucial importance to predict organ-level concentration–time profiles in situation where animal testing is now prohibited, using PBK model information from one chemical substance to inform the development or evaluation of a PBK model for a similar chemical substance [31]. For such purpose, but also to enlarge the use of PBK models, there is today a clear need for user-friendly tools facilitating the implementation of any PBK models, whatever the required number of compartments to consider, whatever the number of connections to account for between compartments in pairs of between compartment and the external medium, and whatever the species-compound combination of interest.…”

“…Multi-compartment models reveal sometimes absolutely necessary, for example in order to finely decipher the internal contamination routes of specific chemical compounds causing damages to only specific organs (Brinkmann et al, 2014; Allen and Weihrauch, 2021; Gestin et al, 2021). Additionally, PBK models can be of crucial importance to predict organ-level concentration–time profiles in situation where animal testing is now prohibited, using PBK model information from one chemical substance to inform the development or evaluation of a PBK model for a similar chemical substance (Thompson et al, 2021). In the perspective to enlarge and facilitate the use of PBK models, namely to include more compartments, to better estimate parameter values from data and to better support a fine deciphering of underlying contamination processes after chemical exposure, there is today a clear need for user-friendly tools.…”