TY - JOUR
KW - Concordance
KW - Drug development
KW - Histopathology
KW - preclinical studies
KW - Statistical modeling
KW - Toxicology
KW - Translational
AU - Peter S. R. Wright
AU - Katharine A. Briggs
AU - Robert Thomas
AU - Graham F. Smith
AU - Gareth Maglennon
AU - Paulius Mikulskis
AU - Melissa Chapman
AU - Nigel Greene
AU - Benjamin U. Phillips
AU - Andreas Bender
AB - 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.
BT - Regulatory Toxicology and Pharmacology
DA - 2023-02-01
DO - 10.1016/j.yrtph.2022.105308
N2 - 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.
PY - 2023
EP - 105308
T2 - Regulatory Toxicology and Pharmacology
TI - Statistical analysis of preclinical inter-species concordance of histopathological findings in the eTOX database
UR - https://www.sciencedirect.com/science/article/pii/S0273230022001957
VL - 138
Y2 - 2023-09-15
SN - 0273-2300
ER -