@article{1339962232a04ef1af0c2b3d048b8048,
title = "A Model-Based Workflow to Benchmark the Clinical Cholestasis Risk of Drugs",
abstract = "We present a generic workflow combining physiology-based computational modeling and in vitro data to assess the clinical cholestatic risk of different drugs systematically. Changes in expression levels of genes involved in the enterohepatic circulation of bile acids were obtained from an in vitro assay mimicking 14 days of repeated drug administration for 10 marketed drugs. These changes in gene expression over time were contextualized in a physiology-based bile acid model of glycochenodeoxycholic acid. The simulated drug-induced response in bile acid concentrations was then scaled with the applied drug doses to calculate the cholestatic potential for each compound. A ranking of the cholestatic potential correlated very well with the clinical cholestasis risk obtained from medical literature. The proposed workflow allows benchmarking the cholestatic risk of novel drug candidates. We expect the application of our workflow to significantly contribute to the stratification of the cholestatic potential of new drugs and to support animal-free testing in future drug development.",
keywords = "DICLOFENAC SODIUM, PHARMACOKINETICS, SINGLE, ACETAMINOPHEN, AZATHIOPRINE, PARACETAMOL, VALPROATE",
author = "V. Baier and O. Clayton and R. Nudischer and H. Cordes and A.R.P. Schneider and C. Thiel and T. Wittenberger and W. Moritz and L.M. Blank and U.P. Neumann and C. Trautwein and J. Kelm and Y. Schrooders and F. Caiment and H. Gmuender and A. Roth and J.V. Castell and J. Kleinjans and L. Kuepfer",
note = "Funding Information: V.B., O.C., R.N., H.C., C.Th., T.W., W.M., L.M.B., J.K., F.C., H.G., A.R., J.V.C., J.K., and L.K. were supported by the European Union Seventh Framework Program HeCaToS (FP7/2007‐2013) under the grant agreement no. 602156, A.R.P.S. was supported by the LiSyM network, Grant Number 031L0039. V.B., L.M.B., and U.P.N. were supported by the Interdisciplinary Centre for Clinical Research within the faculty of Medicine at the RWTH Aachen University (E8‐14). V.B., L.M.B., L.K., C.Tr. and U.P.N. were supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) – Project‐ID 403224013 – SFB 1382. J.C. acknowledges financial support by ISCIII (ref. PI17/01089). Open Access funding enabled and organized by Projekt DEAL. Publisher Copyright: {\textcopyright} 2021 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics",
year = "2021",
month = nov,
doi = "10.1002/cpt.2406",
language = "English",
volume = "110",
pages = "1293--1301",
journal = "Clinical Pharmacology & Therapeutics",
issn = "0009-9236",
publisher = "Wiley",
number = "5",
}