Physiologically Based Modeling of the Effect of Physiological and Anthropometric Variability on Indocyanine Green Based Liver Function Tests

Abstract

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.

Validity and Repeatability Characteristics of a Non-Invasive, Infrared-Based Method Estimating Plasma Indocyanine Green Decay in Healthy Dogs

“…While the explanation may be the poor signal quality in healthy conscious animals, CVs consistently above 20% in all but one dog, and a median CV above 40% would make it an unacceptably performing diagnostic test [18]. It would appear to be unlikely that intra-subject functional hepatic uptake of ICG would vary to such an extent, even if intersubject variability for ICG-CL is affected by differences in physiological function [19].…”

Insights into Intestinal P-glycoprotein Function using Talinolol: A PBPK Modeling Approach

“…The intestinal import process, mediated by OATP2B1, was modeled through irreversible first-order Michaelis-Menten kinetics, while talinolol export reactions follow irreversible mass-action kinetics. Hepatic impairment was modeled as previously described (Köller et al, 2021a,b). Renal impairment was modeled as a stepwise decrease in renal function by scaling all renal processes with the factor , where 1.0 represents normal function and 0.0 represents no renal function.…”

libRoadRunner 2.0: a high performance SBML simulation and analysis library

“…libRoadRunner wraps this low-level interface in user-friendly C and C++ APIs, which, in turn, provide the foundation for critical systems modelling tasks, such as model integration, steady-state analysis and metabolic control analysis ( Somogyi et al , 2015 ).libRoadRunner users usually fall into one of two categories: modellers or tool developers. Modellers use the libRoadRunner tool directly in their research for modelling dynamic systems ( Karagöz et al , 2021 ; Köller et al , 2021a , b ) or for developing new computational approaches such as detecting bistable switches ( Reyes et al , 2022 ) or performing dynamic flux balance analysis ( Watanabe et al , 2018 ). Tool developers, on the other hand, use libRoadRunner as a core SBML handling component in their modular software design, such as in Tellurium ( Choi et al , 2018 ), runBiosimulations ( Shaikh et al , 2021 ), MASSPy ( Haiman et al , 2021 ), SBMLsim ( https://github.com/matthiaskoenig/sbmlsim ), Compucell3D ( Swat et al , 2012 ), PhysiCell ( Ghaffarizadeh et al , 2018 ), pyBioNetFit ( Neumann et al , 2022 ), pyViPR ( Ortega and Lopez, 2020 ) and DIVIPAC ( Nguyen et al , 2015 ).…”