Lhasa Limited shared knowledge shared progress
Publications
  • Highlighted Item:
  • Webinar:
  • Publisher:
    Regulatory Toxicology and Pharmacology
  • Publication Date:
    DEC 2022
  • Reference:
  • DOI:
    /10.1016/j.yrtph.2022.105308
  • PMID:
  • Publication Type:
    Paper
  • Related Products:
  • Scientific Area:
  • Endpoint:
  • Industry Type:
  • Related event:

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

Wright PSR; Briggs K; Thomas R; Smith GF; Maglennon G; Mikuslskis P; Chapman M; Greene N; Phillips BU; Bender A;

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|Cmax| ≤ 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.

Visit site

© 2023 Lhasa Limited | Registered office: Granary Wharf House, 2 Canal Wharf, Leeds, LS11 5PS, UK Tel: +44 (0)113 394 6020
VAT number 396 8737 77 | Lhasa Limited is registered as a charity (290866)| Company Registration Number 01765239 (England and Wales).