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Application of a Rat Liver Drug Bioactivation Transcriptional Response Assay Early in Drug Development That Informs Chemically Reactive Metabolite Formation and Potential for Drug-induced Liver Injury.

Authors
  • Monroe, James J1
  • Tanis, Keith Q2
  • Podtelezhnikov, Alexei A2
  • Nguyen, Truyen1
  • Machotka, Sam V1
  • Lynch, Donna1
  • Evers, Raymond3
  • Palamanda, Jairam3
  • Miller, Randy R3
  • Pippert, Todd1
  • Cabalu, Tamara D3
  • Johnson, Timothy E1
  • Aslamkhan, Amy G1
  • Kang, Wen1
  • Tamburino, Alex M2
  • Mitra, Kaushik1, 4
  • Agrawal, Nancy G B3
  • Sistare, Frank D1
  • 1 Safety Assessment & Laboratory Animal Resources.
  • 2 Human Genetics & Pharmacogenomics.
  • 3 Pharmacokinetics, Pharmacodynamics & Drug Metabolism, Merck & Co., Inc, West Point, Pennsylvania 19486.
  • 4 Janssen Research & Development, LLC, Spring House, PA 19486.
Type
Published Article
Journal
Toxicological Sciences
Publisher
Oxford University Press
Publication Date
Sep 01, 2020
Volume
177
Issue
1
Pages
281–299
Identifiers
DOI: 10.1093/toxsci/kfaa088
PMID: 32559301
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Drug-induced liver injury is a major reason for drug candidate attrition from development, denied commercialization, market withdrawal, and restricted prescribing of pharmaceuticals. The metabolic bioactivation of drugs to chemically reactive metabolites (CRMs) contribute to liver-associated adverse drug reactions in humans that often goes undetected in conventional animal toxicology studies. A challenge for pharmaceutical drug discovery has been reliably selecting drug candidates with a low liability of forming CRM and reduced drug-induced liver injury potential, at projected therapeutic doses, without falsely restricting the development of safe drugs. We have developed an in vivo rat liver transcriptional signature biomarker reflecting the cellular response to drug bioactivation. Measurement of transcriptional activation of integrated nuclear factor erythroid 2-related factor 2 (NRF2)/Kelch-like ECH-associated protein 1 (KEAP1) electrophilic stress, and nuclear factor erythroid 2-related factor 1 (NRF1) proteasomal endoplasmic reticulum (ER) stress responses, is described for discerning estimated clinical doses of drugs with potential for bioactivation-mediated hepatotoxicity. The approach was established using well benchmarked CRM forming test agents from our company. This was subsequently tested using curated lists of commercial drugs and internal compounds, anchored in the clinical experience with human hepatotoxicity, while agnostic to mechanism. Based on results with 116 compounds in short-term rat studies, with consideration of the maximum recommended daily clinical dose, this CRM mechanism-based approach yielded 32% sensitivity and 92% specificity for discriminating safe from hepatotoxic drugs. The approach adds new information for guiding early candidate selection and informs structure activity relationships (SAR) thus enabling lead optimization and mechanistic problem solving. Additional refinement of the model is ongoing. Case examples are provided describing the strengths and limitations of the approach. © The Author(s) 2020. Published by Oxford University Press on behalf of the Society of Toxicology.

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