PMID- 32559301 OWN - NLM STAT- MEDLINE DCOM- 20210721 LR - 20240329 IS - 1096-0929 (Electronic) IS - 1096-6080 (Print) IS - 1096-0929 (Linking) VI - 177 IP - 1 DP - 2020 Sep 1 TI - 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. PG - 281-299 LID - 10.1093/toxsci/kfaa088 [doi] AB - 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. CI - (c) The Author(s) 2020. Published by Oxford University Press on behalf of the Society of Toxicology. FAU - Monroe, James J AU - Monroe JJ AD - Safety Assessment & Laboratory Animal Resources. FAU - Tanis, Keith Q AU - Tanis KQ AD - Human Genetics & Pharmacogenomics. FAU - Podtelezhnikov, Alexei A AU - Podtelezhnikov AA AD - Human Genetics & Pharmacogenomics. FAU - Nguyen, Truyen AU - Nguyen T AD - Safety Assessment & Laboratory Animal Resources. FAU - Machotka, Sam V AU - Machotka SV AD - Safety Assessment & Laboratory Animal Resources. FAU - Lynch, Donna AU - Lynch D AD - Safety Assessment & Laboratory Animal Resources. FAU - Evers, Raymond AU - Evers R AD - Pharmacokinetics, Pharmacodynamics & Drug Metabolism, Merck & Co., Inc, West Point, Pennsylvania 19486. FAU - Palamanda, Jairam AU - Palamanda J AD - Pharmacokinetics, Pharmacodynamics & Drug Metabolism, Merck & Co., Inc, West Point, Pennsylvania 19486. FAU - Miller, Randy R AU - Miller RR AD - Pharmacokinetics, Pharmacodynamics & Drug Metabolism, Merck & Co., Inc, West Point, Pennsylvania 19486. FAU - Pippert, Todd AU - Pippert T AD - Safety Assessment & Laboratory Animal Resources. FAU - Cabalu, Tamara D AU - Cabalu TD AD - Pharmacokinetics, Pharmacodynamics & Drug Metabolism, Merck & Co., Inc, West Point, Pennsylvania 19486. FAU - Johnson, Timothy E AU - Johnson TE AD - Safety Assessment & Laboratory Animal Resources. FAU - Aslamkhan, Amy G AU - Aslamkhan AG AD - Safety Assessment & Laboratory Animal Resources. FAU - Kang, Wen AU - Kang W AD - Safety Assessment & Laboratory Animal Resources. FAU - Tamburino, Alex M AU - Tamburino AM AD - Human Genetics & Pharmacogenomics. FAU - Mitra, Kaushik AU - Mitra K AD - Safety Assessment & Laboratory Animal Resources. AD - Janssen Research & Development, LLC, Spring House, PA 19486. FAU - Agrawal, Nancy G B AU - Agrawal NGB AD - Pharmacokinetics, Pharmacodynamics & Drug Metabolism, Merck & Co., Inc, West Point, Pennsylvania 19486. FAU - Sistare, Frank D AU - Sistare FD AD - Safety Assessment & Laboratory Animal Resources. LA - eng PT - Journal Article PL - United States TA - Toxicol Sci JT - Toxicological sciences : an official journal of the Society of Toxicology JID - 9805461 RN - 0 (Kelch-Like ECH-Associated Protein 1) RN - 0 (NF-E2-Related Factor 2) RN - 0 (Pharmaceutical Preparations) SB - IM MH - Animals MH - *Chemical and Drug Induced Liver Injury MH - Drug Development MH - Kelch-Like ECH-Associated Protein 1 MH - Male MH - NF-E2-Related Factor 2/metabolism MH - *Pharmaceutical Preparations MH - Rats MH - Rats, Sprague-Dawley MH - Rats, Wistar PMC - PMC7553701 OTO - NOTNLM OT - NRF1 OT - NRF2 OT - bioactivation OT - chemically reactive metabolites OT - drug candidate attrition OT - drug safety OT - drug-induced liver injury OT - lead optimization OT - rat liver OT - transcriptional biomarkers EDAT- 2020/06/20 06:00 MHDA- 2021/07/22 06:00 PMCR- 2020/06/19 CRDT- 2020/06/20 06:00 PHST- 2020/06/20 06:00 [pubmed] PHST- 2021/07/22 06:00 [medline] PHST- 2020/06/20 06:00 [entrez] PHST- 2020/06/19 00:00 [pmc-release] AID - 5860030 [pii] AID - kfaa088 [pii] AID - 10.1093/toxsci/kfaa088 [doi] PST - ppublish SO - Toxicol Sci. 2020 Sep 1;177(1):281-299. doi: 10.1093/toxsci/kfaa088.