title: Quantitative in vitro to in vivo extrapolation of tissues toxicity.
abstract: Predicting repeated-dosing in vivo drug toxicity from in vitro testing and omics data gathering requires significant support in bioinformatics, mathematical modeling and statistics. We present here the major aspects of the work devoted within the framework of the European integrated Predict-IV to pharmacokinetic modeling of in vitro experiments, physiologically based pharmacokinetic (PBPK) modeling, mechanistic models of toxicity for the kidney and brain, large scale dose-response analyses methods and biomarker discovery tools. All of those methods have been applied to various extent to the drug datasets developed by the project's partners. Our approach is rather generic and could be adapted to other drugs or drug candidates. It marks a successful integration of the work of the different teams toward a common goal of predictive quantitative in vitro to in vivo extrapolation.
authors: Mathematical Modeling for Systems Toxicology, Université de Technologie de Compiègne, BP 20529, 60205 Compiègne Cedex, France.
authors: Jérémy
authors: J
authors: Hamon
authors: Division of Biostatistics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
authors: Maria
authors: M
authors: Renner
authors: Simcyp Limited (A Certara Company), Blades Enterprise Centre, John Street, Sheffield, UK.
authors: Masoud
authors: M
authors: Jamei
authors: Emergentec Biodevelopment GmbH, Vienna, Austria.
authors: Arno
authors: A
authors: Lukas
authors: Division of Biostatistics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
authors: Annette
authors: A
authors: Kopp-Schneider
authors: Mathematical Modeling for Systems Toxicology, Université de Technologie de Compiègne, BP 20529, 60205 Compiègne Cedex, France; INERIS, DRC/VIVA/METO, Parc ALATA, BP 2, 60550 Verneuil en Halatte, France. Electronic address: frederic.bois@utc.fr.
authors: Frédéric Y
authors: FY
authors: Bois
mesh_terms: D000818:Animals; D018929:Cell Culture Techniques; D002478:Cells, Cultured; D003198:Computer Simulation; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D008954:Models, Biological; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010599:Pharmacokinetics; D011237:Predictive Value of Tests; D013269:Stochastic Processes; D018675:Toxicity Tests
keywords: Bioinformatics; Biomarkers; Dose–response modeling; Physiologically based models; Systems biology