A model-based assay design to reproduce in vivo patterns of acute drug-induced toxicity.

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Title: A model-based assay design to reproduce in vivo patterns of acute drug-induced toxicity.
Author(s): Kuepfer, L
Clayton, O
Thiel, C
Cordes, H
Nudischer, R
Blank, LM
Baier, V
Heymans, S
Caiment, F
Roth, A
Fluri, DA
Kelm, JM
Castell, J
Selevsek, N
Schlapbach, R
Keun, H
Hynes, J
Sarkans, U
Gmuender, H
Herwig, R
Niederer, S
Schuchhardt, J
Segall, M
Kleinjans, J
Item Type: Journal Article
Abstract: For more than a decade pharmaceutical R&D has been hampered by considerable attrition rates during clinical trials. The main reasons for drug failure is related to the lack of efficacy, limitations with respect to ADME (absorption, distribution, metabolism and excretion) properties, and—in approximately 30% of the cases—unforeseen toxicity (Kola and Landis 2004). The majority of adverse drug reactions observed in the clinical phase refer to organ injuries, e.g. of the cardiovascular system, the liver, the central nervous system and skeletal muscle (Cook et al. 2014). This clearly demonstrates the limited predictive accuracy of current preclinical models such as the rodent bioassay in evaluating repeated dose toxicity for predicting human toxic risks. It has been argued that overall, only 43% of toxic effects in humans may be correctly predicted by applying rodent-based safety evaluation protocols due to the fact that these assays tend to generate relatively large numbers of false negative as well as false positive read outs (Hartung 2009).
Publication Date: 29-Aug-2017
Date of Acceptance: 10-Aug-2017
URI: http://hdl.handle.net/10044/1/53952
DOI: https://dx.doi.org/10.1007/s00204-017-2041-7
ISSN: 0340-5761
Publisher: Springer Verlag
Start Page: 553
End Page: 555
Journal / Book Title: Archives of Toxicology
Volume: 92
Issue: 1
Copyright Statement: © The Author(s) 2017. This article is an open access publication
Sponsor/Funder: Commission of the European Communities
Funder's Grant Number: 602156
Keywords: 1115 Pharmacology And Pharmaceutical Sciences
Toxicology
Publication Status: Published
Appears in Collections:Division of Surgery
Division of Cancer
Faculty of Medicine



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