Date: October 15, 2024
Speaker: Matthias König, Ph.D., Group Leader
Affiliation: Konig Lab, Institute for Theoretical Biology, Humboldt-University Berlin
Title: Reproducible digital twins for personalized liver function assessment
Abstract: Essential prerequisites for the practical application and translation of computational models include: i) reproducibility of results; ii) model reusability and extensibility; iii) data availability; and iv) strategies for model stratification and individualization. Here, we present a modeling workflow built around these foundational prerequisites, with a focus on liver function tests.
Despite the paramount significance of liver function assessment in hepatology, reliable quantification remains a clinical challenge. Dynamic liver function tests offer a promising method for non-invasive in vivo assessment of liver function and metabolic phenotyping.
By leveraging whole-body physiologically-based pharmacokinetic (PBPK) models, we’re simulating these tests and positioning PBPK models as digital twins for metabolic phenotyping and liver function assessment. To develop and validate our models, we established the open pharmacokinetics database, PK-DB, containing curated data from 600+ clinical studies [10.1093/nar/gkaa990, 10.3389/fphar.2021.752826]. Our models are individualizable and stratifiable, enabling simulation of lifestyle factors and co-administration effects on drug metabolism. Our models have been instrumental in clinical scenarios: from predicting individual outcomes post-hepatectomy [10.3389/fphys.2021.730418, 10.3389/fphys.2021.757293] to discerning the impact of CYP2D6 gene variants on liver function tests [10.3389/fphar.2022.1029073]. These models are constructed hierarchically, describing metabolic and other biological processes in organs like the liver and kidneys, seamlessly integrated with whole-body physiology.
Notably, all models and data are readily available and reproducible for reuse, encoded in the Systems Biology Markup Language (SBML) [10.15252/msb.20199110]. We will provide an overview of these PBPK models and demonstrate how SBML and FAIR principles can facilitate model development, coupling, and reuse.
[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.