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Prediction of Survival After Partial Hepatectomy Using a Physiologically Based Pharmacokinetic Model of Indocyanine Green Liver Function Tests.

ABSTRACT: The evaluation of hepatic function and functional capacity of the liver are essential tasks in hepatology as well as in hepatobiliary surgery. Indocyanine green (ICG) is a widely applied test compound that is used in clinical routine to evaluate hepatic function. Important questions for the functional evaluation with ICG in the context of hepatectomy are how liver disease such as cirrhosis alters ICG elimination, and if postoperative survival can be predicted from preoperative ICG measurements. Within this work a physiologically based pharmacokinetic (PBPK) model of ICG was developed and applied to the prediction of the effects of a liver resection under various degrees of cirrhosis. For the parametrization of the computational model and validation of model predictions a database of ICG pharmacokinetic data was established. The model was applied (i) to study the effect of liver cirrhosis and liver resection on ICG pharmacokinetics; and (ii) to evaluate the model-based prediction of postoperative ICG-R15 (retention ratio 15 min after administration) as a measure for postoperative outcome. Key results are the accurate prediction of changes in ICG pharmacokinetics caused by liver cirrhosis and postoperative changes of ICG-elimination after liver resection, as validated with a wide range of data sets. Based on the PBPK model, individual survival after liver resection could be classified, demonstrating its potential value as a clinical tool.

SUBMITTER: Koller A

PROVIDER: S-EPMC8646028 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Accurate evaluation of liver function is a central task in hepatology. Dynamic liver function tests (DLFT) based on the time-dependent elimination of a test substance provide an important tool for such a functional assessment. These tests are used in the diagnosis and monitoring of liver disease as well as in the planning of hepatobiliary surgery. A key challenge in the evaluation of liver function with DLFTs is the large inter-individual variability. Indocyanine green (ICG) is a widely applied test compound used for the evaluation of liver function. After an intravenous administration, pharmacokinetic (PK) parameters are calculated from the plasma disappearance curve of ICG which provide an estimate of liver function. The hepatic elimination of ICG is affected by physiological factors such as hepatic blood flow or binding of ICG to plasma proteins, anthropometric factors such as body weight, age, and sex, or the protein amount of the organic anion-transporting polypeptide 1B3 (OATP1B3) mediating the hepatic uptake of ICG. Being able to account for and better understand these various sources of inter-individual variability would allow to improve the power of ICG based DLFTs and move toward an individualized evaluation of liver function. Within this work we systematically analyzed the effect of various factors on ICG elimination by the means of computational modeling. For the analysis, a recently developed and validated physiologically based pharmacokinetics (PBPK) model of ICG distribution and hepatic elimination was utilized. Key results are (i) a systematic analysis of the variability in ICG elimination due to hepatic blood flow, cardiac output, OATP1B3 abundance, liver volume, body weight and plasma bilirubin level; (ii) the evaluation of the inter-individual variability in ICG elimination via a large in silico cohort of n = 100,000 subjects based on the NHANES cohort with special focus on stratification by age, sex, and body weight; (iii) the evaluation of the effect of various degrees of cirrhosis on variability in ICG elimination. The presented results are an important step toward individualizing liver function tests by elucidating the effects of confounding physiological and anthropometric parameters in the evaluation of liver function via ICG.

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Prediction of Survival After Partial Hepatectomy Using a Physiologically Based Pharmacokinetic Model of Indocyanine Green Liver Function Tests.

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