دورية أكاديمية
أعرض في EDS

Statistical analysis of preclinical inter-species concordance of histopathological findings in the eTOX database.

التفاصيل البيبلوغرافية
العنوان: Statistical analysis of preclinical inter-species concordance of histopathological findings in the eTOX database.
المؤلفون: Wright PSR; University of Cambridge, Centre for Molecular Science Informatics, Department of Chemistry, Cambridge, United Kingdom. Electronic address: psrw2@cam.ac.uk., Briggs KA; Lhasa Limited, Leeds, United Kingdom., Thomas R; Lhasa Limited, Leeds, United Kingdom., Smith GF; AstraZeneca, Data Science and AI, Clinical Pharmacology and Safety Sciences, R&D, Cambridge, United Kingdom., Maglennon G; AstraZeneca, Oncology Pathology, Clinical Pharmacology and Safety Sciences, R&D, Melbourn, United Kingdom., Mikulskis P; AstraZeneca, Imaging and Data Analytics, Clinical Pharmacology & Safety Sciences, R&D, Gothenburg, Sweden., Chapman M; AstraZeneca, Toxicology, Clinical Pharmacology and Safety Sciences, R&D, Melbourn, United Kingdom., Greene N; AstraZeneca, Data Science and Artificial Intelligence, Clinical Pharmacology and Safety Sciences, R&D, Boston, MA, USA., Phillips BU; AstraZeneca, Data Sciences and Quantitative Biology, Discovery Sciences, Cambridge Biomedical Campus, Cambridge, United Kingdom., Bender A; University of Cambridge, Centre for Molecular Science Informatics, Department of Chemistry, Cambridge, United Kingdom. Electronic address: andreas.bender@cantab.net.
المصدر: Regulatory toxicology and pharmacology : RTP [Regul Toxicol Pharmacol] 2023 Feb; Vol. 138, pp. 105308. Date of Electronic Publication: 2022 Dec 05.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Elsevier Country of Publication: Netherlands NLM ID: 8214983 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1096-0295 (Electronic) Linking ISSN: 02732300 NLM ISO Abbreviation: Regul Toxicol Pharmacol Subsets: MEDLINE
أسماء مطبوعة: Publication: <2003>- : Amsterdam : Elsevier
Original Publication: New York : Academic Press, [c1981-
مواضيع طبية MeSH: Drug-Related Side Effects and Adverse Reactions*, Animals ; Female ; Rats ; Dogs ; Databases, Factual ; Research Design
مستخلص: Preclinical inter-species concordance can increase the predictivity of observations to the clinic, potentially reducing drug attrition caused by unforeseen adverse events. We quantified inter-species concordance of histopathological findings and target organ toxicities across four preclinical species in the eTOX database using likelihood ratios (LRs). This was done whilst only comparing findings between studies with similar compound exposure (Δ|C max | ≤ 1 log-unit), repeat-dosing duration, and animals of the same sex. We discovered 24 previously unreported significant inter-species associations between histopathological findings encoded by the HPATH ontology. More associations with strong positive concordance (33% LR+ > 10) relative to strong negative concordance (12.5% LR- < 0.1) were identified. Of the top 10 most positively concordant associations, 60% were computed between different histopathological findings indicating potential differences in inter-species pathogenesis. We also observed low inter-species target organ toxicity concordance. For example, liver toxicity concordance in short-term studies between female rats and dogs observed an average LR+ of 1.84, and an average LR- of 0.73. This was corroborated by similarly low concordance between rodents and non-rodents for 75 candidate drugs in AstraZeneca. This work provides new statistically significant associations between preclinical species, but finds that concordance is rare, particularly between the absence of findings.
Competing Interests: Declaration of competing interest The authors declare the following financial/personal relationships which may be considered as potential competing interests: PW is funded by the National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs). KB, and RT are employees of Lhasa Limited. GF, GM, PM, MC, NG, and BP are employees of AstraZeneca. AB is a co-founder of Healx Ltd., and PharmEnable Ltd., and is a consultant for various pharmaceutical and consumer goods companies.
(Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
معلومات مُعتمدة: NC/R001952/1 United Kingdom NC3RS_ National Centre for the Replacement, Refinement and Reduction of Animals in Research
فهرسة مساهمة: Keywords: Concordance; Drug development; Histopathology; Preclinical studies; Statistical modeling; Toxicology; Translational
تواريخ الأحداث: Date Created: 20221208 Date Completed: 20230208 Latest Revision: 20230215
رمز التحديث: 20231215
DOI: 10.1016/j.yrtph.2022.105308
PMID: 36481279
قاعدة البيانات: MEDLINE
الوصف
تدمد:1096-0295
DOI:10.1016/j.yrtph.2022.105308