Adrian Köller, Jan Grzegorzewski, Matthias König
Institute for Theoretical Biology, Humboldt-University Berlin, Invalidenstraße 110, Berlin 10115, Germany
Objectives: The evaluation of hepatic function and functional capacity of the liver are essential tasks in hepatology, especially in the context of liver surgery. Dynamic liver function tests (DLFT) enable quantitative assessment of the organ’s functional reserve for selected functions by analyzing the kinetics of the metabolization of a specific test substrate (hepatic elimination) [1,2]. DLFTs using various test substances have been investigated in the past providing information about in vivo hepatic clearance, e.g., indocyanine green [3], caffeine [4], or methacetin [2,5]. Indocyanine Green (ICG) is used in clinical routine to evaluate hepatic function, especially in the context of hepatic surgery. Important questions for the functional evaluation with ICG in the context of liver resection are (i) how liver disease, especially cirrhosis alters ICG elimination, and (ii) if post-operative survival can be predicted from pre-operative ICG measurements.
Methods: The aim of our study was to use computational modeling to derive basic information for a better understanding of the indocyanine green liver function tests and factors influencing its results. Based on the recently established pharmacokinetics database PK-DB [6] a high quality dataset of clinical ICG measurements was established. A physiological based pharmacokinetics models (PBPK) for ICG was developed and validated using the dataset. Determining liver function using ICG is based on its plasma-concentration time course after administration. Using the clinical or predicted plasma time course pharmacokinetic parameters are calculated, with the most commonly used parameters being: the ICG plasma disappearance rate (ICG-PDR), the ICG-clearance, the ICG retention ratio 15 minutes after administration (ICG-R15), and the ICG half life time.
Results: Within this work a physiological-based model of ICG pharmacokinetics was developed and applied to the prediction of liver resection under various degrees of cirrhosis. For the parametrization and validation of the model a database of ICG pharmacokinetic data was established. The model was applied to study (i) the effect of liver disease, specifically liver cirrhosis, on ICG pharmacokinetics; and (ii) the effect of liver resection on ICG-elimination and the value of ICG as a predictive measure for postoperative outcome. The model performance could be validated on a wide range of clinical studies. The model is able to accurately predict changes in ICG pharmacokinetics caused by liver cirrhosis. Furthermore, the model is able to accurately predict postoperative changes of ICG-elimination after liver resection and outcome of liver resection, showing its potential value as a clinical tool.
Conclusions: We could establish and validate a physiological-based model of ICG pharmacokinetics in the context of hepatic surgery. In conclusion, we developed a computational model for ICG based liver function evaluation which could become a valuable tool for liver surgery. Because the model takes into account factors like hepatic blood flow, degree of cirrhosis, plasma proteins, and planned resection volume, an accurate prediction of postoperative liver functional capacity in agreement with clinical data can be achieved. With comprehensive information about the patient, the model can be adjusted accordingly and could provide an improved individualized prediction of the future remnant liver function.
References:
[1] Herold, C.; Berg, P.; Kupfal, D.; Becker, D.; Schuppan, D.; Hahn, E. G. & Schneider, H. T.; Parameters of microsomal and cytosolic liver function but not of liver perfusion predict portal vein velocity in noncirrhotic patients with chronic hepatitis C. Digestive diseases and sciences, 2000, 45, 2233-2237
[2] Rubin, T.M., Heyne, K., Luchterhand, A., Bednarsch, J., Vondran, F.W., Polychronidis, G., Malinowski, M., Nikolic, A., Tautenhahn, H.M., Jara, M. and Wünsch, T., 2017. Kinetic validation of the LiMAx test during 10 000 intravenous 13C-methacetin breath tests. Journal of breath research, 12(1), p.016005.
[3] De Gasperi, A.; Mazza, E. & Prosperi, M. Indocyanine green kinetics to assess liver function: Ready for a clinical dynamic assessment in major liver surgery? World journal of hepatology, 10.4254/wjh.v8.i7.355, 2016, 8, 355-367
[4] Renner, E.; Wietholtz, H.; Huguenin, P.; Arnaud, M. J. & Preisig, R. Caffeine: a model compound for measuring liver function. Hepatology, 1984, 4, 38-46
[5] Gorowska-Kowolik, K.; Chobot, A. & Kwiecien, J. 13C Methacetin Breath Test for Assessment of Microsomal Liver Function: Methodology and Clinical Application. Gastroenterology research and practice, 2017, 2017, 7397840
[6] Jan Grzegorzewski, Janosch Brandhorst, Kathleen Green, Dimitra Eleftheriadou, Yannick Duport, Florian Barthorscht, Adrian Köller, Danny Yu Jia Ke, Sara De Angelis, Matthias König, PK-DB: pharmacokinetics database for individualized and stratified computational modeling, Nucleic Acids Research, Volume 49, Issue D1, 8 January 2021, Pages D1358–D1364
Reference: PAGE 29 (2021) Abstr 9841 [www.page-meeting.org/?abstract=9841]
Poster: Clinical Applications