Computational Modeling of Dynamical Liver Function Tests: LiMAx
König M., Wünsch T., Lill D., Lock JF., Mohr J., Taheri P., Timmer J., Stockmann M.
Computational Modeling of Dynamical Liver Function Tests: LiMAx and Methacetin Breath Test (MBT)
Modeling LiMAx liver function test
Assessment of liver function is a key task in hepatology but accurate quantification of hepatic function has remained a clinical challenge. Dynamic liver function tests are a promising tool for the non-invasive evaluation of liver function in vivo. One class of such tests are breath tests based on the conversion of 13C-labeled substrates by the liver to 13CO2 subsequently measured in the breath. A commonly applied substrate is 13C-methacetin, converted to paracetamol and 13CO2 via cytochrome P450 1A2 (CYP1A2), used orally in the methacetin breath test (MBT) and intravenously in the LiMAx test. An important clinical question is which factors can affect MBT and LiMAx results. The aim of our study was to answer this question using computational modeling to derive basic information for a better understanding of the methacetin breath test and factors influencing its results.
A physiological based pharmacokinetics (PBPK) model for 13C-methacetin breath tests including absorption, distribution, metabolism and elimination of 13C-methacetin, paracetamol, and 13C-bicarbonate/13CO2 was developed. The model correctly predicts data from more than 20 clinical studies after oral and intravenous application under various dosing regimens of paracetamol, 13C-bicarbonate, and 13C-methacetin, based on retrospective analysis. Model predictions were validated based on data from multiple studies consisting of 13C-bicarbonate kinetics, LiMAx dosing study and retrospective analysis of LiMAx data from healthy smokers and non-smokers. Sensitivity analysis was performed to identify key factors influencing MBT and LiMAx.The model was applied to study the effect of clinically relevant parameters like CYP1A2 content, hepatic perfusion or lifestyle factors like smoking on LiMAx. In summary, we present a valuable tool for the evaluation of dynamical liver function tests based on 13C-methacetin.