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

Köller, Adrian; Grzegorzewski, Jan; Tautenhahn, Hans‐Michael; König, Matthias

doi:10.3389/fphys.2021.730418

Cited by 8 publications

(17 citation statements)

References 59 publications

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“…Liver cirrhosis was modeled by a combination of functional tissue loss and shunts. For a detailed description of the model we refer to Köller et al ( 2021 ).…”

Section: Resultsmentioning

confidence: 99%

“…Simulations were performed using sbmlsim (König, 2021a ) based on the high-performance SBML simulator libroadrunner (Somogyi et al, 2015 ). We refer to Köller et al ( 2021 ) for more details on the computational model, the model simulations, the data curation process, the calculation of pharmacokinetic parameters, and the implementation of liver cirrhosis. No model changes were performed compared to the model described in Köller et al ( 2021 ).…”

Section: Methodsmentioning

confidence: 99%

“…Measurements from both methods correlate well (Purcell et al, 2006 ). From the concentration-time profile a set of pharmacokinetic parameters can be calculated (e.g., ICG clearance, plasma disappearance rate (ICG-PDR), retention ratio after 15 min (ICG-R15), ICG half-life), which provide estimates of liver function based on the ICG elimination capacity of the liver (Sakka, 2018 ; Köller et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

“…Physiological factors such as hepatic blood flow, binding to plasma proteins, or the amount of transport protein mediating the hepatic ICG uptake can influence the elimination of ICG. Furthermore, ICG elimination is generally reduced in liver disease and altered by surgical interventions such as partial hepatectomy (Köller et al, 2021 ). For example liver cirrhosis, which is the end-stage of most chronic liver diseases, 2reduces ICG-elimination and increases half-life of ICG significantly.…”

Section: Introductionmentioning

confidence: 99%

“…Within this work we systematically investigated the individual contribution of these factors to the large inter-individual variability in liver function tests based on ICG using a recently developed and validated physiologically based pharmacokinetics (PBPK) model of ICG (Köller et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

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

Köller

Grzegorzewski²,

König³

2021

Front. Physiol.

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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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“…Liver cirrhosis was modeled by a combination of functional tissue loss and shunts. For a detailed description of the model we refer to Köller et al ( 2021 ).…”

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Köller

Grzegorzewski²,

König³

2021

Front. Physiol.

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libRoadRunner 2.0: a high performance SBML simulation and analysis library

et al. 2022

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Motivation This paper presents libRoadRunner 2.0, an extensible, high-performance, cross-platform, open-source software library for the simulation and analysis of models expressed using the Systems Biology Markup Language (SBML). Results libRoadRunner is a self-contained library, able to run either as a component inside other tools via its C ++, C and Python APIs, or interactively through its Python or Julia interface. libRoadRunner uses a custom Just-In-Time (JIT) compiler built on the widely-used LLVM JIT compiler framework. It compiles SBML-specified models directly into native machine code for a large variety of processors, making it fast enough to simulate extremely large models or repeated runs in reasonable timeframes. libRoadRunner is flexible, supporting the bulk of the SBML specification (except for delay and nonlinear algebraic equations) as well as several SBML extensions such as hierarchical composition and probability distributions. It offers multiple deterministic and stochastic integrators, as well as tools for steady-state, sensitivity, stability and structural analyses. Availability libRoadRunner binary distributions for Windows, Mac OS, and Linux, Julia and Python bindings, source code, and documentation are all available at https://github.com/sys-bio/roadrunner, and Python bindings are also available via pip. The source code can be compiled for the supported systems as well as in principle any system supported by LLVM-13, such as ARM-based computers like the Raspberry Pi. The library is licensed under the Apache License Version 2.0.

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

Mallol,

Grzegorzewski,

Tautenhahn

et al. 2023

Preprint

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Talinolol is a cardioselective beta-blocker that was previously used to treat heart failure and myocardial infarction. Following the development of new, more effective beta-blockers with better study results, talinolol is now only used clinically for the treatment of arterial hypertension. In basic science, talinolol continues to be used as a test substance due to its pharmacokinetics. Its intestinal absorption is determined by uptake by the organic anion transporting polypeptide 2B1 (OATP2B1) and efflux via P-glycoprotein (P-gp). Talinolol can be taken up via OATP1B1 in the liver, where it enters the enterohepatic circulation. Talinolol is excreted unchanged in the urine and feces. Talinolol is widely used as a probe drug for the intestinal efflux transporter P-gp, which plays a critical role in protecting against potentially toxic substances and facilitating the elimination of xenobiotics. In this work, an extensive database of talinolol pharmacokinetics was established and used to develop and validate a physiologically based pharmacokinetic (PBPK) model of talinolol for P-gp phenotyping. The model was used to investigate the influence of several factors on talinolol pharmacokinetics: (i) inhibition of P-gp via drug-drug interaction; (i) genetic polymorphisms of P-gp; (iii) activity of OATP2B1 and OATP1B1; (iv) effect of comorbidity, namely hepatic and renal impairment; and (v) site-specific distribution of P-gp and OATP2B1 in the intestine. The model accurately predicts the concentration-time profile of talinolol after oral or intravenous administration of single and multiple dosing. Furthermore, the model accurately describes the effect of genetic variants of P-gp on the pharmacokinetics of talinolol, the effect of inhibition of P-gp, the effect of renal impairment, as well as site-specific infusion of talinolol in the intestine. The detailed description of the intestinal absorption of talinolol and the predictions of talinolol pharmacokinetics as a function of hepatorenal impairment provide valuable clinical insights for metabolic phenotyping with talinolol. Both the model and the database are freely available for reuse.

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

Cited by 8 publications

References 59 publications

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

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

libRoadRunner 2.0: a high performance SBML simulation and analysis library

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

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