Prediction of dose-hepatotoxic response in humans based on toxicokinetic/toxicodynamic modeling with or without in vivo data: A case study with acetaminophen

In the present legislations, the use of methods alternative to animal testing is explicitly encouraged, to use animal testing only 'as a last resort' or to ban it. The use of alternative methods to replace kinetics or repeated dose in vivo tests is a challenging issue. We propose here a strategy based on modeling to analyze in vitro tests and on QSAR (Quantitative Structure Activity Relationship) models to calibrate a dose-response model predicting hepatotoxicity. The dose response consists in calibrating and coupling a PBPK (Physiologically-based pharmacokinetic) model with a toxicodynamic model for cell viability. We applied our strategy to acetaminophen and compared three different ways to calibrate the PBPK model: only with in vitro and in silico methods, using rat data or using all available data including data on humans. Some estimates of kinetic parameters differed substantially among the three calibration processes, but, at the end, the three models were quite comparable in terms of liver toxicity predictions and close to the usual range of human overdose. For the model based on alternative methods, such behaviour resulted from an overestimated renal elimination rate which compensated for the underestimation of the metabolism rate. Our study points out that the coupling of alternative methods is a rather complex issue and that more studies are needed in order to assess the general reliability of these approaches.

PERY Alexandre;  BROCHOT Céline;  ZEMAN Florence;  MOMBELLI E;  DESMOTS Sophie;  PAVAN Manuela;  FIORAVANZO Elena;  ZALDIVAR COMENGES José M; 

2013-05-08

ELSEVIER IRELAND LTD

JRC79258

0378-4274,   

http://www.sciencedirect.com/science/article/pii/S037842741300146X,    https://publications.jrc.ec.europa.eu/repository/handle/JRC79258,   

10.1016/j.toxlet.2013.03.032,