title: Prediction of dose-hepatotoxic response in humans based on toxicokinetic/toxicodynamic modeling with or without in vivo data: a case study with acetaminophen.
abstract: 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 in vitro tests and 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, the good adequation with the two other models resulted from an overestimated renal elimination rate which compensated for the underestimation of the metabolism rate. Our study points out that toxicokinetics/toxicodynamics approaches, based on alternative methods and modelling only, can predict in vivo liver toxicity with accuracy comparable to in vivo methods.
authors.affiliation: Unité « Modèles pour l'écotoxicologie et la toxicologie » (METO), INERIS, Parc Alata BP2, 60550 Verneuil-en-Halatte, France. alexandre.pery@ineris.fr
authors.forename: Alexandre R R
authors.initials: AR
authors.lastname: Péry
authors.forename: Céline
authors.initials: C
authors.lastname: Brochot
authors.forename: Florence A
authors.initials: FA
authors.lastname: Zeman
authors.forename: Enrico
authors.initials: E
authors.lastname: Mombelli
authors.forename: Sophie
authors.initials: S
authors.lastname: Desmots
authors.forename: Manuela
authors.initials: M
authors.lastname: Pavan
authors.forename: Elena
authors.initials: E
authors.lastname: Fioravanzo
authors.forename: José-Manuel
authors.initials: JM
authors.lastname: Zaldívar
mesh_terms: D000082:Acetaminophen / Q000737:chemistry / Q000493:pharmacokinetics* / Q000633:toxicity*; D000700:Analgesics / Q000737:chemistry / Q000493:pharmacokinetics* / Q000633:toxicity*; D000826:Animal Testing Alternatives; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism*; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D005544:Forecasting; D006801:Humans; D008297:Male; D008954:Models, Biological; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000700:Analgesics; D000082:Acetaminophen