PMID- 33338378
OWN - NLM
STAT- MEDLINE
DCOM- 20210923
LR  - 20210923
IS  - 1520-5010 (Electronic)
IS  - 0893-228X (Linking)
VI  - 34
IP  - 2
DP  - 2021 Feb 15
TI  - New Associations between Drug-Induced Adverse Events in Animal Models and Humans 
      Reveal Novel Candidate Safety Targets.
PG  - 438-451
LID - 10.1021/acs.chemrestox.0c00311 [doi]
AB  - To improve our ability to extrapolate preclinical toxicity to humans, there is a 
      need to understand and quantify the concordance of adverse events (AEs) between 
      animal models and clinical studies. In the present work, we discovered 3011 
      statistically significant associations between preclinical and clinical AEs 
      caused by drugs reported in the PharmaPendium database of which 2952 were new 
      associations between toxicities encoded by different Medical Dictionary for 
      Regulatory Activities terms across species. To find plausible and testable 
      candidate off-target drug activities for the derived associations, we 
      investigated the genetic overlap between the genes linked to both a preclinical 
      and a clinical AE and the protein targets found to interact with one or more 
      drugs causing both AEs. We discuss three associations from the analysis in more 
      detail for which novel candidate off-target drug activities could be identified, 
      namely, the association of preclinical mutagenicity readouts with clinical 
      teratospermia and ovarian failure, the association of preclinical reflexes 
      abnormal with clinical poor-quality sleep, and the association of preclinical 
      psychomotor hyperactivity with clinical drug withdrawal syndrome. Our analysis 
      successfully identified a total of 77% of known safety targets currently tested 
      in in vitro screening panels plus an additional 431 genes which were proposed for 
      investigation as future safety targets for different clinical toxicities. This 
      work provides new translational toxicity relationships beyond AE term-matching, 
      the results of which can be used for risk profiling of future new chemical 
      entities for clinical studies and for the development of future in vitro safety 
      panels.
FAU - Giblin, Kathryn A
AU  - Giblin KA
AUID- ORCID: 0000-0003-2446-6326
AD  - Centre for Molecular Informatics, Department of Chemistry, University of 
      Cambridge, Lensfield Road, Cambridge CB2 1EW, United Kingdom.
AD  - Medicinal Chemistry, Research and Early Development, Oncology R&D, AstraZeneca, 
      Cambridge CB4 0WG, United Kingdom.
FAU - Basili, Danilo
AU  - Basili D
AD  - Centre for Molecular Informatics, Department of Chemistry, University of 
      Cambridge, Lensfield Road, Cambridge CB2 1EW, United Kingdom.
FAU - Afzal, Avid M
AU  - Afzal AM
AD  - Data Sciences and Quantitative Biology, Discovery Sciences, R&D, AstraZeneca, 
      Cambridge CB4 0WG, United Kingdom.
FAU - Rosenbrier-Ribeiro, Lyn
AU  - Rosenbrier-Ribeiro L
AD  - Safety Platforms, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, 
      Cambridge CB4 0WG, United Kingdom.
FAU - Greene, Nigel
AU  - Greene N
AD  - Data Science and Artificial Intelligence, Clinical Pharmacology and Safety 
      Sciences, R&D, AstraZeneca, Boston, Massachusetts 02451, United States.
FAU - Barrett, Ian
AU  - Barrett I
AD  - Data Sciences and Quantitative Biology, Discovery Sciences, R&D, AstraZeneca, 
      Cambridge CB4 0WG, United Kingdom.
FAU - Hughes, Samantha J
AU  - Hughes SJ
AD  - Medicinal Chemistry, Research and Early Development, Oncology R&D, AstraZeneca, 
      Cambridge CB4 0WG, United Kingdom.
FAU - Bender, Andreas
AU  - Bender A
AUID- ORCID: 0000-0002-6683-7546
AD  - Centre for Molecular Informatics, Department of Chemistry, University of 
      Cambridge, Lensfield Road, Cambridge CB2 1EW, United Kingdom.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20201218
PL  - United States
TA  - Chem Res Toxicol
JT  - Chemical research in toxicology
JID - 8807448
RN  - 0 (Pharmaceutical Preparations)
SB  - IM
MH  - *Adverse Drug Reaction Reporting Systems
MH  - Animals
MH  - Databases, Factual
MH  - Humans
MH  - Models, Animal
MH  - Molecular Structure
MH  - Pharmaceutical Preparations/*chemistry
EDAT- 2020/12/19 06:00
MHDA- 2021/09/24 06:00
CRDT- 2020/12/18 20:08
PHST- 2020/12/19 06:00 [pubmed]
PHST- 2021/09/24 06:00 [medline]
PHST- 2020/12/18 20:08 [entrez]
AID - 10.1021/acs.chemrestox.0c00311 [doi]
PST - ppublish
SO  - Chem Res Toxicol. 2021 Feb 15;34(2):438-451. doi: 10.1021/acs.chemrestox.0c00311. 
      Epub 2020 Dec 18.