Systems biology aims to understand living organisms through mathematically modeling their behaviors at different organizational levels, ranging from molecules to populations. Modeling involves several steps, from determining the model purpose to developing the mathematical model, implementing it computationally, simulating the model's behavior, evaluating, and refining the model. Importantly, model simulation results must be reproducible, ensuring that other researchers can obtain the same results after writing the code de novo and/or using different software tools. Guidelines to increase model reproducibility have been published. However, reproducibility remains a major challenge in this field. In this paper, we tackle this challenge for physiologically-based pharmacokinetic (PBPK) models, which represent the pharmacokinetics of chemicals following exposure in humans or animals. We summarize recommendations for PBPK model reporting that should apply during model development and implementation, in order to ensure model reproducibility and comprehensibility. We make a proposal aiming to harmonize abbreviations used in PBPK models. To illustrate these recommendations, we present an original and reproducible PBPK model code in MATLAB, alongside an example of MATLAB code converted to Systems Biology Markup Language format using MOCCASIN. As directions for future improvement, more tools to convert computational PBPK models from different software platforms into standard formats would increase the interoperability of these models. The application of other systems biology standards to PBPK models is encouraged. This work is the result of an interdisciplinary collaboration involving the ELIXIR systems biology community. More interdisciplinary collaborations like this would facilitate further harmonization and application of good modeling practices in different systems biology fields.

Department of Bioinformatics BiGCaT School of Nutrition and Translational Research in Metabolism Faculty of Health Medicine and Life Sciences Maastricht University P O Box 616 6200 MD Maastricht The Netherlands

Department of Biotechnology and Systems Biology National Institute of Biology Večna pot 121 1000 Ljubljana Slovenia

Department of Life Sciences National Bioinformatics Infrastructure Sweden SciLifeLab Chalmers University of Technology Kemigården 1 Gothenburg SE 412 96 Sweden

ELIXIR Wellcome Genome Campus Hinxton Cambridgeshire CB10 1SD United Kingdom

Institute of Biochemistry and Molecular Genetics Faculty of Medicine University of Ljubljana Zaloška 4 1000 Ljubljana Slovenia

International Clinical Research Center St Anne's University Hospital Brno Pekařská 53 656 91 Brno Czech Republic

Laboratory of Bioprocess Engineering Wageningen University and Research Droevendaalsesteeg 1 6708 PB Wageningen The Netherlands

Laboratory of Systems and Synthetic Biology Wageningen University and Research Agrotechnology and Food Sciences Stippeneng 4 6708 WE Wageningen The Netherlands

Loschmidt Laboratories Department of Experimental Biology and RECETOX Faculty of Science Masaryk University Kamenice 5 625 00 Brno Czech Republic

RECETOX Faculty of Science Masaryk University Kotlarska 2 611 37 Brno Czech Republic

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Response to Letter to Editor by A. Derbalah et al.: the role of automation in enhancing reproducibility and interoperability of PBPK models