A Model-Based Workflow to Benchmark the Clinical Cholestasis Risk of Drugs

V. Baier; O. Clayton; R. Nudischer; H. Cordes; A.R.P. Schneider; C. Thiel; T. Wittenberger; W. Moritz; L.M. Blank; U.P. Neumann; C. Trautwein; J. Kelm; Y. Schrooders; F. Caiment; H. Gmuender; A. Roth; J.V. Castell; J. Kleinjans; L. Kuepfer

doi:10.1002/cpt.2406

A Model-Based Workflow to Benchmark the Clinical Cholestasis Risk of Drugs

V. Baier, O. Clayton, R. Nudischer, H. Cordes, A.R.P. Schneider, C. Thiel, T. Wittenberger, W. Moritz, L.M. Blank, U.P. Neumann, C. Trautwein, J. Kelm, Y. Schrooders, F. Caiment, H. Gmuender, A. Roth, J.V. Castell, J. Kleinjans, L. Kuepfer^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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.

Original language	English
Pages (from-to)	1293-1301
Number of pages	9
Journal	Clinical Pharmacology & Therapeutics
Volume	110
Issue number	5
Early online date	1 Sept 2021
DOIs	https://doi.org/10.1002/cpt.2406
Publication status	Published - Nov 2021

Keywords

DICLOFENAC SODIUM
PHARMACOKINETICS
SINGLE
ACETAMINOPHEN
AZATHIOPRINE
PARACETAMOL
VALPROATE

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Baier, V., Clayton, O., Nudischer, R., Cordes, H., Schneider, A. R. P., Thiel, C., Wittenberger, T., Moritz, W., Blank, L. M., Neumann, U. P., Trautwein, C., Kelm, J., Schrooders, Y., Caiment, F., Gmuender, H., Roth, A., Castell, J. V., Kleinjans, J., & Kuepfer, L. (2021). A Model-Based Workflow to Benchmark the Clinical Cholestasis Risk of Drugs. Clinical Pharmacology & Therapeutics, 110(5), 1293-1301. https://doi.org/10.1002/cpt.2406

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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",

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Baier, V, Clayton, O, Nudischer, R, Cordes, H, Schneider, ARP, Thiel, C, Wittenberger, T, Moritz, W, Blank, LM, Neumann, UP, Trautwein, C, Kelm, J, Schrooders, Y, Caiment, F, Gmuender, H, Roth, A, Castell, JV, Kleinjans, J & Kuepfer, L 2021, 'A Model-Based Workflow to Benchmark the Clinical Cholestasis Risk of Drugs', Clinical Pharmacology & Therapeutics, vol. 110, no. 5, pp. 1293-1301. https://doi.org/10.1002/cpt.2406

TY - JOUR

T1 - A Model-Based Workflow to Benchmark the Clinical Cholestasis Risk of Drugs

AU - Baier, V.

AU - Clayton, O.

AU - Nudischer, R.

AU - Cordes, H.

AU - Schneider, A.R.P.

AU - Thiel, C.

AU - Wittenberger, T.

AU - Moritz, W.

AU - Blank, L.M.

AU - Neumann, U.P.

AU - Trautwein, C.

AU - Kelm, J.

AU - Schrooders, Y.

AU - Caiment, F.

AU - Gmuender, H.

AU - Roth, A.

AU - Castell, J.V.

AU - Kleinjans, J.

AU - Kuepfer, L.

N1 - 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: © 2021 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics

PY - 2021/11

Y1 - 2021/11

N2 - 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.

AB - 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.

KW - DICLOFENAC SODIUM

KW - PHARMACOKINETICS

KW - SINGLE

KW - ACETAMINOPHEN

KW - AZATHIOPRINE

KW - PARACETAMOL

KW - VALPROATE

U2 - 10.1002/cpt.2406

DO - 10.1002/cpt.2406

M3 - Article

C2 - 34462909

SN - 0009-9236

VL - 110

SP - 1293

EP - 1301

JO - Clinical Pharmacology & Therapeutics

JF - Clinical Pharmacology & Therapeutics

IS - 5

ER -