Filter and export

Publications

What is a Publication?
80 Publications visible to you, out of a total of 80
Data-driven personalization of a physiologically based pharmacokinetic model for caffeine: A systematic assessment

Abstract (Expand)

Physiologically based pharmacokinetic (PBPK) models have been proposed as a tool for more accurate individual pharmacokinetic (PK) predictions and model-informed precision dosing, but their application … in clinical practice is still rare. This study systematically assesses the benefit of using individual patient information to improve PK predictions. A PBPK model of caffeine was stepwise personalized by using individual data on (1) demography, (2) physiology, and (3) cytochrome P450 (CYP) 1A2 phenotype of 48 healthy volunteers participating in a single-dose clinical study. Model performance was benchmarked against a caffeine base model simulated with parameters of an average individual. In the first step, virtual twins were generated based on the study subjects' demography (height, weight, age, sex), which implicated the rescaling of average organ volumes and blood flows. The accuracy of PK simulations improved compared with the base model. The percentage of predictions within 0.8-fold to 1.25-fold of the observed values increased from 45.8% (base model) to 57.8% (Step 1). However, setting physiological parameters (liver blood flow determined by magnetic resonance imaging, glomerular filtration rate, hematocrit) to measured values in the second step did not further improve the simulation result (59.1% in the 1.25-fold range). In the third step, virtual twins matching individual demography, physiology, and CYP1A2 activity considerably improved the simulation results. The percentage of data within the 1.25-fold range was 66.15%. This case study shows that individual PK profiles can be predicted more accurately by considering individual attributes and that personalized PBPK models could be a valuable tool for model-informed precision dosing approaches in the future.

Authors: Rebekka Fendt, Ute Hofmann, Annika Schneider, Elke Schaeffeler, Rolf Burghaus, Ali Yilmaz, Lars Mathias Blank, Reinhold Kerb, Jan-Frederik Schlender, Matthias Schwab, Lars Kuepfer

Date Published: 30th May 2021

Publication Type: Journal

Delta-Like Ligand 4 Modulates Liver Damage by Down-Regulating Chemokine Expression

Abstract

Not specified

Authors: Zhe Shen, Yan Liu, Bedair Dewidar, Junhao Hu, Ogyi Park, Teng Feng, Chengfu Xu, Chaohui Yu, Qi Li, Christoph Meyer, Iryna Ilkavets, Alexandra Müller, Carolin Stump-Guthier, Stefan Munker, Roman Liebe, Vincent Zimmer, Frank Lammert, Peter R. Mertens, Hai Li, Peter ten Dijke, Hellmut G. Augustin, Jun Li, Bin Gao, Matthias P. Ebert, Steven Dooley, Youming Li, Hong-Lei Weng

Date Published: 1st Jul 2016

Publication Type: Not specified

Digital twin demonstrates significance of biomechanical growth control in liver regeneration after partial hepatectomy

Abstract

Not specified

Authors: Stefan Hoehme, Seddik Hammad, Jan Boettger, Brigitte Begher-Tibbe, Petru Bucur, Eric Vibert, Rolf Gebhardt, Jan G. Hengstler, Dirk Drasdo

Date Published: 2023

Publication Type: Journal

Disentangling molecular mechanisms regulating sensitization of interferon alpha signal transduction.

Abstract (Expand)

Tightly interlinked feedback regulators control the dynamics of intracellular responses elicited by the activation of signal transduction pathways. Interferon alpha (IFNalpha) orchestrates antiviral … responses in hepatocytes, yet mechanisms that define pathway sensitization in response to prestimulation with different IFNalpha doses remained unresolved. We establish, based on quantitative measurements obtained for the hepatoma cell line Huh7.5, an ordinary differential equation model for IFNalpha signal transduction that comprises the feedback regulators STAT1, STAT2, IRF9, USP18, SOCS1, SOCS3, and IRF2. The model-based analysis shows that, mediated by the signaling proteins STAT2 and IRF9, prestimulation with a low IFNalpha dose hypersensitizes the pathway. In contrast, prestimulation with a high dose of IFNalpha leads to a dose-dependent desensitization, mediated by the negative regulators USP18 and SOCS1 that act at the receptor. The analysis of basal protein abundance in primary human hepatocytes reveals high heterogeneity in patient-specific amounts of STAT1, STAT2, IRF9, and USP18. The mathematical modeling approach shows that the basal amount of USP18 determines patient-specific pathway desensitization, while the abundance of STAT2 predicts the patient-specific IFNalpha signal response.

Authors: F. Kok, M. Rosenblatt, M. Teusel, T. Nizharadze, V. Goncalves Magalhaes, C. Dachert, T. Maiwald, A. Vlasov, M. Wasch, S. Tyufekchieva, K. Hoffmann, G. Damm, D. Seehofer, T. Boettler, M. Binder, J. Timmer, M. Schilling, U. Klingmuller

Date Published: 23rd Jul 2020

Publication Type: Journal

Downregulation of ECM1 in hepatocytes as a damage response to liver injury

Abstract

Not specified

Authors: Yujia Li, Weronika Pioronska, Zeribe Nwosu, Weiguo Fan, MatthiasP.A. Ebert, Steven Dooley, Sai Wang

Date Published: 2022

Publication Type: Journal

Powered by
 (v.1.16.1)
About FAIRDOM | About LiSyM | Funding and Programmes | Credits | Terms & Conditions | Imprint
Copyright © 2008 - 2024 The University of Manchester and HITS gGmbH