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

TL;DR

This paper compares classical and multiscale liver models to improve in-vitro to in-vivo extrapolation of acetaminophen toxicity, highlighting the advantages of detailed spatial-temporal modeling over traditional methods.

Contribution

It introduces a multiscale digital twin model for liver toxicity prediction, providing a novel approach to improve extrapolation accuracy over classical models.

Findings

Multiscale liver model outperforms classical models in certain extrapolation scenarios.

Mechanistic models incorporating liver microarchitecture improve toxicity predictions.

Comparison shows when detailed models are advantageous over Cmax or AUC based strategies.

Abstract

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.