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In Vitro Approach to Assess the Potential for Risk of Idiosyncratic Adverse Reactions Caused by Candidate Drugs

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†̂ DMPK Innovative Medicine, AstraZeneca, Mölndal, 431 83, Sweden
Discovery DMPK, AstraZeneca, Wilmington, Delaware, United States
§ DMPK Innovative Medicine, AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom
Global Safety Assessment, AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom
Discovery Sciences, AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom
# Discovery DMPK, AstraZeneca, Loughborough, Leicestershire LE11 5RH, United Kingdom
*Tel: +46 31 776 25 67. E-mail: [email protected]
Cite this: Chem. Res. Toxicol. 2012, 25, 8, 1616–1632
Publication Date (Web):May 31, 2012
https://doi.org/10.1021/tx300091x
Copyright © 2012 American Chemical Society

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    Abstract

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    Idiosyncratic adverse drug reactions (IADRs) in humans can result in a broad range of clinically significant toxicities leading to attrition during drug development as well as postlicensing withdrawal or labeling. IADRs arise from both drug and patient related mechanisms and risk factors. Drug related risk factors, resulting from parent compound or metabolites, may involve multiple contributory mechanisms including organelle toxicity, effects related to compound disposition, and/or immune activation. In the current study, we evaluate an in vitro approach, which explored both cellular effects and covalent binding (CVB) to assess IADR risks for drug candidates using 36 drugs which caused different patterns and severities of IADRs in humans. The cellular effects were tested in an in vitro Panel of five assays which quantified (1) toxicity to THLE cells (SV40 T-antigen-immortalized human liver epithelial cells), which do not express P450s, (2) toxicity to a THLE cell line which selectively expresses P450 3A4, (3) cytotoxicity in HepG2 cells in glucose and galactose media, which is indicative of mitochondrial injury, (4) inhibition of the human bile salt export pump, BSEP, and (5) inhibition of the rat multidrug resistance associated protein 2, Mrp2. In addition, the CVB Burden was estimated by determining the CVB of radiolabeled compound to human hepatocytes and factoring in both the maximum prescribed daily dose and the fraction of metabolism leading to CVB. Combining the aggregated results from the in vitro Panel assays with the CVB Burden data discriminated, with high specificity (78%) and sensitivity (100%), between 27 drugs, which had severe or marked IADR concern, and 9 drugs, which had low IADR concern, we propose that this integrated approach has the potential to enable selection of drug candidates with reduced propensity to cause IADRs in humans.

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    Structures and maximum daily doses in μmol; replicates and confidence intervals for all compounds in the Mrp2, BSEP, MitoTox, THLE-Null, and THLE-3A4 assays; data analysis of aggregated in vitro Panel scores and levels of IADR concern; and plot of the aggregated in vitro Panel score vs maximum daily dose. This material is available free of charge via the Internet at http://pubs.acs.org.

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    48. Sabine Weber, Alexander L. Gerbes. Challenges and Future of Drug-Induced Liver Injury Research—Laboratory Tests. International Journal of Molecular Sciences 2022, 23 (11) , 6049. https://doi.org/10.3390/ijms23116049
    49. Maryam Mirahmad, Reyhaneh Sabourian, Mohammad Mahdavi, Bagher Larijani, Maliheh Safavi. In vitro cell-based models of drug-induced hepatotoxicity screening: progress and limitation. Drug Metabolism Reviews 2022, 54 (2) , 161-193. https://doi.org/10.1080/03602532.2022.2064487
    50. M. Teresa Donato, Nuria Jiménez, María Pelechá, Laia Tolosa. Oxidative-stress and long-term hepatotoxicity: comparative study in Upcyte human hepatocytes and hepaRG cells. Archives of Toxicology 2022, 96 (4) , 1021-1037. https://doi.org/10.1007/s00204-022-03236-y
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    64. María Teresa Donato, Laia Tolosa. High-Content Screening for the Detection of Drug-Induced Oxidative Stress in Liver Cells. Antioxidants 2021, 10 (1) , 106. https://doi.org/10.3390/antiox10010106
    65. Thomas Steger-Hartmann, Marian Raschke. Translating in vitro to in vivo and animal to human. Current Opinion in Toxicology 2020, 23-24 , 6-10. https://doi.org/10.1016/j.cotox.2020.02.003
    66. Seung-Hwan Jung, Wonseok Lee, Seung-Hyun Park, Kang-Yo Lee, You-Jin Choi, Soohee Choi, Dongmin Kang, Sinri Kim, Tong-Shin Chang, Soon-Sun Hong, Byung-Hoon Lee. Diclofenac impairs autophagic flux via oxidative stress and lysosomal dysfunction: Implications for hepatotoxicity. Redox Biology 2020, 37 , 101751. https://doi.org/10.1016/j.redox.2020.101751
    67. Maria Bandookwala, Kavya Sri Nemani, Bappaditya Chatterjee, Pinaki Sengupta. Reactive Metabolites: Generation and Estimation with Electrochemistry Based Analytical Strategy as an Emerging Screening Tool. Current Analytical Chemistry 2020, 16 (7) , 811-825. https://doi.org/10.2174/1573411016666200131154202
    68. Leah M. Norona, Aaron Fullerton, Chris Lawson, Leslie Leung, Jochen Brumm, Tomomi Kiyota, Jonathan Maher, Cyrus Khojasteh, William R. Proctor. In vitro assessment of farnesoid X receptor antagonism to predict drug-induced liver injury risk. Archives of Toxicology 2020, 94 (9) , 3185-3200. https://doi.org/10.1007/s00204-020-02804-4
    69. Kazuko Inoue, Hitoshi Mizuo, Tomomi Ishida, Takafumi Komori, Kazutomi Kusano. Bioactivation of diclofenac in human hepatocytes and the proposed human hepatic proteins modified by reactive metabolites. Xenobiotica 2020, 50 (8) , 919-928. https://doi.org/10.1080/00498254.2020.1728592
    70. Paul A. Walker, Stephanie Ryder, Andrea Lavado, Clive Dilworth, Robert J. Riley. The evolution of strategies to minimise the risk of human drug-induced liver injury (DILI) in drug discovery and development. Archives of Toxicology 2020, 94 (8) , 2559-2585. https://doi.org/10.1007/s00204-020-02763-w
    71. Lixin Ke, Cuncun Lu, Rui Shen, Tingting Lu, Bin Ma, Yunpeng Hua. Knowledge Mapping of Drug-Induced Liver Injury: A Scientometric Investigation (2010–2019). Frontiers in Pharmacology 2020, 11 https://doi.org/10.3389/fphar.2020.00842
    72. Amit S. Kalgutkar, James P. Driscoll. Is there enough evidence to classify cycloalkyl amine substituents as structural alerts?. Biochemical Pharmacology 2020, 174 , 113796. https://doi.org/10.1016/j.bcp.2020.113796
    73. Nicola J. Stagg, Hanan N. Ghantous, Robert Roth, Kenneth L. Hastings. Predictivity/Translatability of Toxicities Observed in Nonclinical Toxicology Studies to Clinical Safety Outcomes in Drug Development: Case Examples. International Journal of Toxicology 2020, 39 (2) , 141-150. https://doi.org/10.1177/1091581819894281
    74. Richard J. Weaver, Eric A. Blomme, Amy E. Chadwick, Ian M. Copple, Helga H. J. Gerets, Christopher E. Goldring, Andre Guillouzo, Philip G. Hewitt, Magnus Ingelman-Sundberg, Klaus Gjervig Jensen, Satu Juhila, Ursula Klingmüller, Gilles Labbe, Michael J. Liguori, Cerys A. Lovatt, Paul Morgan, Dean J. Naisbitt, Raymond H. H. Pieters, Jan Snoeys, Bob van de Water, Dominic P. Williams, B. Kevin Park. Managing the challenge of drug-induced liver injury: a roadmap for the development and deployment of preclinical predictive models. Nature Reviews Drug Discovery 2020, 19 (2) , 131-148. https://doi.org/10.1038/s41573-019-0048-x
    75. Jose Castro-Perez, Chandra Prakash. Recent advances in mass spectrometric and other analytical techniques for the identification of drug metabolites. 2020, 39-71. https://doi.org/10.1016/B978-0-12-820018-6.00002-8
    76. Stanley E Lazic, Dominic P Williams. Improving drug safety predictions by reducing poor analytical practices. Toxicology Research and Application 2020, 4 , 239784732097863. https://doi.org/10.1177/2397847320978633
    77. Akinori Takemura, Kousei Ito. The trends in predicting drug-induced liver injury. Folia Pharmacologica Japonica 2020, 155 (6) , 401-405. https://doi.org/10.1254/fpj.20049
    78. Kosuke Anan, Yasuyoshi Iso, Takuya Oguma, Kenji Nakahara, Shinji Suzuki, Takahiko Yamamoto, Eriko Matsuoka, Hisanori Ito, Gaku Sakaguchi, Shigeru Ando, Kenji Morimoto, Naoki Kanegawa, Yasuto Kido, Tomoyuki Kawachi, Tamio Fukushima, Ard Teisman, Vijay Urmaliya, Deborah Dhuyvetter, Herman Borghys, Nigel Austin, An Van Den Bergh, Peter Verboven, Francois Bischoff, Harrie J. M. Gijsen, Yoshinori Yamano, Ken-ichi Kusakabe. Trifluoromethyl Dihydrothiazine‐Based β‐Secretase (BACE1) Inhibitors with Robust Central β‐Amyloid Reduction and Minimal Covalent Binding Burden. ChemMedChem 2019, 14 (22) , 1894-1910. https://doi.org/10.1002/cmdc.201900478
    79. Fredrik Bergström, Bo Lindmark. Accelerated drug discovery by rapid candidate drug identification. Drug Discovery Today 2019, 24 (6) , 1237-1241. https://doi.org/10.1016/j.drudis.2019.03.026
    80. Michael D. Aleo, Jiri Aubrecht, Paul D. Bonin, Deborah A. Burt, Jennifer Colangelo, Lina Luo, Shelli Schomaker, Rachel Swiss, Simon Kirby, Greg C. Rigdon, Pinky Dua. Phase I study of PF‐04895162, a Kv7 channel opener, reveals unexpected hepatotoxicity in healthy subjects, but not rats or monkeys: clinical evidence of disrupted bile acid homeostasis. Pharmacology Research & Perspectives 2019, 7 (1) https://doi.org/10.1002/prp2.467
    81. Claire G. Jeong, Gianni Dal Negro, Spiro Getsios, Jason E. Ekert. Application of complex in vitro models (CIVMs) in drug discovery for safety testing and disease modeling. 2019, 121-158. https://doi.org/10.1016/B978-0-12-813671-3.00005-0
    82. J Gerry Kenna, Rebecca Ram. Safety Assessment of Pharmaceuticals. 2019, 167-176. https://doi.org/10.1016/B978-0-12-813697-3.00020-2
    83. Nobuyuki Kakutani, Toyomichi Nanayama, Yukihiro Nomura. Novel risk assessment of reactive metabolites from discovery to clinical stage. The Journal of Toxicological Sciences 2019, 44 (3) , 201-211. https://doi.org/10.2131/jts.44.201
    84. Jingyu Hu, Yide Yang, Zhengzhao Lou, Chuanfa Ni, Jinbo Hu. Fluoro‐Hydroxylation of gem ‐Difluoroalkenes: Synthesis of 18 O‐labeled α‐CF 3 Alcohols. Chinese Journal of Chemistry 2018, 36 (12) , 1202-1208. https://doi.org/10.1002/cjoc.201800426
    85. Kathy Archibald, Katya Tsaioun, J. Gerry Kenna, Pandora Pound. Better science for safer medicines: the human imperative. Journal of the Royal Society of Medicine 2018, 111 (12) , 433-438. https://doi.org/10.1177/0141076818812783
    86. J. Gerry Kenna, Kunal S. Taskar, Christina Battista, David L. Bourdet, Kim L.R. Brouwer, Kenneth R. Brouwer, David Dai, Christoph Funk, Michael J. Hafey, Yurong Lai, Jonathan Maher, Y. Anne Pak, Jenny M. Pedersen, Joseph W. Polli, A. David Rodrigues, Paul B. Watkins, Kyunghee Yang, Robert W. Yucha, . Can Bile Salt Export Pump Inhibition Testing in Drug Discovery and Development Reduce Liver Injury Risk? An International Transporter Consortium Perspective. Clinical Pharmacology & Therapeutics 2018, 104 (5) , 916-932. https://doi.org/10.1002/cpt.1222
    87. J. Gerry Kenna, Jack Uetrecht. Do In Vitro Assays Predict Drug Candidate Idiosyncratic Drug-Induced Liver Injury Risk?. Drug Metabolism and Disposition 2018, 46 (11) , 1658-1669. https://doi.org/10.1124/dmd.118.082719
    88. Anja Ekdahl, Lars Weidolf, Matthew Baginski, Yoshio Morikawa, Richard A. Thompson, Ian D. Wilson. The metabolic fate of fenclozic acid in chimeric mice with a humanized liver. Archives of Toxicology 2018, 92 (9) , 2819-2828. https://doi.org/10.1007/s00204-018-2274-0
    89. Sara Moses, Ulf Andersson, Martin Billger. Preclinical Toxicology Evaluation. 2018, 499-526. https://doi.org/10.1002/9783527801756.ch18
    90. S. Cyrus Khojasteh, Grover P. Miller, Kaushik Mitra, Ivonne M. C. M. Rietjens. Biotransformation and bioactivation reactions – 2017 literature highlights. Drug Metabolism Reviews 2018, 50 (3) , 221-255. https://doi.org/10.1080/03602532.2018.1473875
    91. Monicah A Otieno, Jan Snoeys, Wing Lam, Avi Ghosh, Mark R Player, Alessandro Pocai, Rhys Salter, Damir Simic, Hollie Skaggs, Bhanu Singh, Heng-Keang Lim. Fasiglifam (TAK-875): Mechanistic Investigation and Retrospective Identification of Hazards for Drug Induced Liver Injury. Toxicological Sciences 2018, 163 (2) , 374-384. https://doi.org/10.1093/toxsci/kfx040
    92. Anastassia Karageorgis, Stephen C. Lenhard, Brittany Yerby, Mikael F. Forsgren, Serguei Liachenko, Edvin Johansson, Mark A. Pilling, Richard A. Peterson, Xi Yang, Dominic P. Williams, Sharon E. Ungersma, Ryan E. Morgan, Kim L. R. Brouwer, Beat M. Jucker, Paul D. Hockings, . A multi-center preclinical study of gadoxetate DCE-MRI in rats as a biomarker of drug induced inhibition of liver transporter function. PLOS ONE 2018, 13 (5) , e0197213. https://doi.org/10.1371/journal.pone.0197213
    93. Falgun Shah, Alex Medvedev, Anne Mai Wassermann, Marian Brodney, Liying Zhang, Sergei Makarov, Robert V Stanton. The Identification of Pivotal Transcriptional Factors Mediating Cell Responses to Drugs With Drug-Induced Liver Injury Liabilities. Toxicological Sciences 2018, 162 (1) , 177-188. https://doi.org/10.1093/toxsci/kfx231
    94. Eleni Kotsampasakou, Sankalp Jain, Daniela Digles, Gerhard F. Ecker. Transporters in Hepatotoxicity. 2018, 145-174. https://doi.org/10.1002/9781119282594.ch6
    95. Monicah A. Otieno, Jinping Gan, William Proctor. Status and Future of 3D Cell Culture in Toxicity Testing. 2018, 249-261. https://doi.org/10.1007/978-1-4939-7677-5_12
    96. Axel Pähler. Reactive Metabolite Assessment in Drug Discovery and Development in Support of Safe Drug Design. 2018, 263-281. https://doi.org/10.1007/978-1-4939-7677-5_13
    97. Deborah S. Light, Michael D. Aleo, J. Gerry Kenna. Interpretation, Integration, and Implementation of In Vitro Assay Data: The Predictive Toxicity Challenge. 2018, 345-364. https://doi.org/10.1007/978-1-4939-7677-5_17
    98. J. Gerry Kenna, John C. Waterton, Andreas Baudy, Aleksandra Galetin, Catherine D. G. Hines, Paul Hockings, Manishkumar Patel, Daniel Scotcher, Steven Sourbron, Sabina Ziemian, Gunnar Schuetz. Noninvasive Preclinical and Clinical Imaging of Liver Transporter Function Relevant to Drug-Induced Liver Injury. 2018, 627-651. https://doi.org/10.1007/978-1-4939-7677-5_30
    99. Franck A. Atienzar, Jean-Marie Nicolas. Prediction of Human Liver Toxicity Using In Vitro Assays: Limitations and Opportunities. 2018, 125-150. https://doi.org/10.1007/978-1-4939-7677-5_7
    100. Zhen Ren, Si Chen, Baitang Ning, Lei Guo. Use of Liver-Derived Cell Lines for the Study of Drug-Induced Liver Injury. 2018, 151-177. https://doi.org/10.1007/978-1-4939-7677-5_8
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