@article{ref1,
title="Prediction of human drug-induced liver injury (DILI) in relation to oral doses and blood concentrations",
journal="Archives of toxicology",
year="2019",
author="Albrecht, Wiebke and Kappenberg, Franziska and Brecklinghaus, Tim and Stoeber, Regina and Marchan, Rosemarie and Zhang, Mian and Ebbert, Kristina and Kirschner, Hendrik and Grinberg, Marianna and Leist, Marcel and Moritz, Wolfgang and Cadenas, Cristina and Ghallab, Ahmed and Reinders, Jörg and Vartak, Nachiket and van Thriel, Christoph and Golka, Klaus and Tolosa, Laia and Castell, José V. and Damm, Georg and Seehofer, Daniel and Lampen, Alfonso and Braeuning, Albert and Buhrke, Thorsten and Behr, Anne-Cathrin and Oberemm, Axel and Gu, Xiaolong and Kittana, Naim and van de Water, Bob and Kreiling, Reinhard and Fayyaz, Susann and van Aerts, Leon and Smedsrød, Bård and Ellinger-Ziegelbauer, Heidrun and Steger-Hartmann, Thomas and Gundert-Remy, Ursula and Zeigerer, Anja and Ullrich, Anett and Runge, Dieter and Lee, Serene M. L. and Schiergens, Tobias S. and Kuepfer, Lars and Aguayo-Orozco, Alejandro and Sachinidis, Agapios and Edlund, Karolina and Gardner, Iain and Rahnenführer, Jörg and Hengstler, Jan G.",
volume="93",
number="6",
pages="1609-1637",
abstract="Drug-induced liver injury (DILI) cannot be accurately predicted by animal models. In addition, currently available in vitro methods do not allow for the estimation of hepatotoxic doses or the determination of an acceptable daily intake (ADI). To overcome this limitation, an in vitro/in silico method was established that predicts the risk of human DILI in relation to oral doses and blood concentrations. This method can be used to estimate DILI risk if the maximal blood concentration (C<sub>max</sub>) of the test compound is known. Moreover, an ADI can be estimated even for compounds without information on blood concentrations. To systematically optimize the in vitro system, two novel test performance metrics were introduced, the toxicity separation index (TSI) which quantifies how well a test differentiates between hepatotoxic and non-hepatotoxic compounds, and the toxicity estimation index (TEI) which measures how well hepatotoxic blood concentrations in vivo can be estimated. In vitro test performance was optimized for a training set of 28 compounds, based on TSI and TEI, demonstrating that (1) concentrations where cytotoxicity first becomes evident in vitro (EC<sub>10</sub>) yielded better metrics than higher toxicity thresholds (EC<sub>50</sub>); (2) compound incubation for 48 h was better than 24 h, with no further improvement of TSI after 7 days incubation; (3) metrics were moderately improved by adding gene expression to the test battery; (4) evaluation of pharmacokinetic parameters demonstrated that total blood compound concentrations and the 95%-population-based percentile of C<sub>max</sub> were best suited to estimate human toxicity. With a support vector machine-based classifier, using EC<sub>10</sub> and C<sub>max</sub> as variables, the cross-validated sensitivity, specificity and accuracy for hepatotoxicity prediction were 100, 88 and 93%, respectively. Concentrations in the culture medium allowed extrapolation to blood concentrations in vivo that are associated with a specific probability of hepatotoxicity and the corresponding oral doses were obtained by reverse modeling. Application of this in vitro/in silico method to the rat hepatotoxicant pulegone resulted in an ADI that was similar to values previously established based on animal experiments. In conclusion, the proposed method links oral doses and blood concentrations of test compounds to the probability of hepatotoxicity.<p /> <p>Language: en</p>",
language="en",
issn="0340-5761",
doi="10.1007/s00204-019-02492-9",
url="http://dx.doi.org/10.1007/s00204-019-02492-9"
}