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

Abstract

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.

Cardiotoxicity Hazard and Risk Characterization of ToxCast Chemicals Using Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes from Multiple Donors

“…The lower the MOS, the higher degree of possible overlap between the concentration that induces a response in vitro and the estimated in vivo human exposure. Human C max values were sourced and extracted from the PharmaPendium database . For each drug with available human pharmacokinetic data and activity in at least one phenotype, the MOS for the median individual was derived by dividing the median individual POD for the critical end point by the population median C max estimate (with outliers removed).…”

The Ontology of Biological Attributes (OBA) - Computational Traits for the Life Sciences

“…OBA trait terms imported into EFO can facilitate computational drug target identification via the Open Targets Platform 60 . For example, OBA, in tandem with other ontologies, has proved useful for computational drug target identification in a study of drug-induced adverse events in animal models 61 .…”

Perspective for Discovery of Small Molecule IL-6 Inhibitors through Study of Structure–Activity Relationships and Molecular Docking

“…The two major categories of toxicity associated with mAbs are target-related effects and target-independent toxicities (including immunogenicity) . Target-related adverse events (AEs) can include either cellular effects that are intended to occur at the intended target tissue or cellular effects that are unintended and occur as a result of mAb interactions with the target antigen at an unintended tissue (e.g., antitumor mAbs targeting epidermal growth factor receptor leading to skin AEs). , Immunogenicity is the emergence of an antidrug antibody (ADA) host response to the therapeutic mAb, and is a risk of all therapeutic mAbs, which occurs regardless of the therapeutic mAb target . ADAs have the potential to cause infusion reactions, alter pharmacokinetic parameters, reduce therapeutic efficacy, and decrease target binding (including hypersensitivity) .…”