Disease Maps - Reproducible physiological based pharmacokinetics models using COMBINE standards

Описание: Matthias König (https://livermetabolism.com, [email protected])
Humboldt-University Berlin, Institute for Theoretical Biology, Berlin
Keywords: liver, PBPK, pharmacokinetics, reproducibility, FAIR
Reproducibility, reusability, and transparency are essential for the practical application and translational impact of computational models in drug development and precision medicine. In this breakout session, we present a robust modeling workflow that adheres to these principles, facilitating the development and validation of physiologically based pharmacokinetic (PBPK) models.

Our approach is built on the open pharmacokinetics database PK-DB, which aggregates curated pharmacokinetic data from over 600 clinical studies [10.1093/nar/gkaa990, 10.3389/fphar.2021.752826]. This resource enables the creation of individualizable and stratifiable PBPK models, allowing for the simulation of lifestyle factors, co-administration effects, and genetic variations on drug metabolism. These models have been successfully applied to predict individual drug responses post-hepatectomy [10.3389/fphys.2021.730418, 10.3389/fphys.2021.757293] and to assess the impact of genetic polymorphisms on pharmacokinetics [10.3389/fphar.2022.1029073].

Constructed hierarchically, our models integrate metabolic and physiological processes in organs such as the liver and kidneys within a whole-body framework. They are FAIR-compliant, encoded in the Systems Biology Markup Language (SBML) for seamless reuse, interoperability, and reproducibility [10.15252/msb.20199110].

During this talk, we will demonstrate our PBPK modeling workflows and showcase tools that facilitate model development, coupling, and reuse, including PK-DB, sbml4humans, sbmlutils, cy3sbml, libsbgnpy, and FAIR indicators. Attendees will gain insights into how COMBINE standards and FAIR principles can drive reproducible and extensible pharmacokinetic modeling in systems medicine.

[1] PK-DB: pharmacokinetics database for individualized and stratified computational modeling. Grzegorzewski J, Brandhorst J, Green K, Eleftheriadou D, Duport Y, Barthorscht F, Köller A, Ke DYJ, De Angelis S, König M. Nucleic Acids Res. 2021 Jan 8;49(D1):D1358-D1364. doi:10.1093/nar/gkaa990.
[2] Pharmacokinetics of caffeine: A systematic analysis of reported data for application in metabolic phenotyping and liver function testing. Jan Grzegorzewski, Florian Bartsch, Adrian Köller, and Matthias König. Frontiers in Pharmacology 2022, Vol12. doi:10.3389/fphar.2021.752826.
[3] Prediction of survival after hepatectomy using a physiologically based pharmacokinetic model of indocyanine green liver function tests. Adrian Köller, Jan Grzegorzewski, Michael Tautenhahn, Matthias König. Front. Physiol., 22 November 2021. doi:10.3389/fphys.2021.730418.
[4] Physiologically based modeling of the effect of physiological and anthropometric variability on indocyanine green based liver function tests. Adrian Köller, Jan Grzegorzewski and Matthias König. Front Physiol. 2021 Nov 22;12:757293. doi:10.3389/fphys.2021.757293.
[5] Physiologically based pharmacokinetic (PBPK) modeling of the role of CYP2D6 polymorphism for metabolic phenotyping with dextromethorphan. Grzegorzewski, J., Brandhorst, J., König, M. Front Pharmacol. 2022 Oct 24;13:1029073. doi:10.3389/fphar.2022.1029073
[6] SBML Level 3: an extensible format for the exchange and reuse of biological models. SM Keating, D Waltemath, M König, F Zhang, A Dräger, C Chaouiya, FT Bergmann, A Finney, CS Gillespie, T Helikar, S Hoops, RS Malik-Sheriff, SL Moodie, II Moraru, CJ Myers, A Naldi, BG Olivier, S Sahle, JC Schaff, LP Smith, MJ Swat, DT, L Watanabe, DJ Wilkinson, ML Blinov, K Begley, JR Faeder, HF Gómez, TM Hamm, Y Inagaki, W Liebermeister, AL Lister, D Lucio, E Mjolsness, CJ Proctor, K Raman, N Rodriguez, CA Shaffer, BE Shapiro, J Stelling, N Swainston, N Tanimura, J Wagner, M Meier-Schellersheim, HM Sauro, B Palsson, H Bolouri, H Kitano, Akira Funahashi, H Hermjakob, JC Doyle M Hucka, and SBML Community members. Mol Syst Biol. 2020;16(8):e9110. doi:10.15252/msb.20199110
[7] Specifications of Standards in Systems and Synthetic Biology: Status and Developments in 2022 and the COMBINE meeting 2022. M. König, P. Gleeson, M. Golebiewski, T. Gorochowski, M. Hucka, S. Keating, C. Myers, D. Nickerson, F. Schreiber. J Integr Bioinform. 2023 Mar 29;20(1).. doi:10.1515/jib-2023-0004.