New Associations between Drug-Induced Adverse Events in Animal Models and Humans Reveal Novel Candidate Safety Targets

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.