In-vitro to in-vivo acetaminophen hepatotoxicity extrapolation using classical schemes, pharmaco-dynamic models and a multiscale spatial-temporal liver twin - Laboratoire Jacques-Louis Lions Accéder directement au contenu
Article Dans Une Revue (Data Paper) Frontiers in Bioengineering and Biotechnology Année : 2023

In-vitro to in-vivo acetaminophen hepatotoxicity extrapolation using classical schemes, pharmaco-dynamic models and a multiscale spatial-temporal liver twin

Résumé

In vitro to in vivo extrapolation represents a critical challenge in toxicology. In this paper we explore extrapolation strategies for acetaminophen (APAP) based on mechanistic models, comparing classical homogeneous compartment pharmaco-dynamic (PD) models and a multiscale digital twin model resolving liver microarchitecture at cellular resolution. The models integrate consensus detoxification reactions in each individual hepatocyte. We study the consequences of the two model types on the extrapolation and show in which cases these models perform better than the classical extrapolation strategy that is based either on the maximal drug concentration (Cmax) or the area under the pharmaco-kinetic curve (AUC) of the drug blood concentration. We find that an CL-model based on a well-mixed blood compartment is sufficient to correctly predict the in vivo toxicity from in vitro data. However, the ST-model that integrates more experimental information requires a change of at least one parameter to obtain the same prediction, indicating that spatial compartmentalization may indeed be an important factor.
Fichier principal
Vignette du fichier
2210.08796.pdf (1.81 Mo) Télécharger le fichier
Origine : Publication financée par une institution

Dates et versions

hal-03941544 , version 1 (16-01-2023)

Identifiants

Citer

Jules Dichamp, Geraldine Cellière, Ahmed Ghallab, Reham Hassan, Noemie Boissier, et al.. In-vitro to in-vivo acetaminophen hepatotoxicity extrapolation using classical schemes, pharmaco-dynamic models and a multiscale spatial-temporal liver twin. Frontiers in Bioengineering and Biotechnology, In press, 11, ⟨10.3389/fbioe.2023.1049564⟩. ⟨hal-03941544⟩
73 Consultations
39 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More