Sutherland, Jeffrey, Yonchev, Dimitar, Fekete, Alexander and Urban, Laszlo (2023) A novel preclinical secondary pharmacology resource illuminates target-adverse drug reaction associations of marketed drugs. Nature Communications, online (online). pp. 1-17.

Abstract

In vitro secondary pharmacology assays are an important tool for predicting clinical adverse drug reactions of investigational drugs. We tested 1958 marketed or withdrawn drugs using 200 safety pharmacology assays and compared our results to public and subscription resources to determine their on- and off-target effects. The aim of this study was the validation of (off)-target engagement and ADR associations. Approximately 95% of all results, and 36% of active results (AC50 < 1 µM) were unique to our database, with low quantitative agreement and bias towards higher activity on the subset of results appearing in public resources. By annotating drugs with their efficacious free maximal concentration in blood (free Cmax), we found 684 novel off-target activities at concentrations within 10 fold of free Cmax (potentially physiological). Comparing the known ADRs of drugs to assay activity revealed that 64% of putative ADRs linked to target activity in key literature reviews were not statistically significant in our dataset. Systematic analysis of all target vs. ADR pairs identified several novel associations with literature support, including α2C adrenergic receptor (ADRA2C) inhibition vs. hallucination and aggression, D3 dopamine receptor (DRD3) inhibition vs. tardive dyskinesia and progresterone receptor (PGR) agonism vs. hyperpigmentation disorders. Finally, the database was used to propose candidate mechanisms for known drug ADRs based on newly described off-target activities. Examples include M1/M2 muscarinic receptor (CHRM1/CHRM2) inhibition of trimipramine and zolpidem vs. accommodation disorder, and D1 dopamine receptor inhibition (DRD1) of citalopram vs. movement disorders. The Secondary Pharmacology Database (SPD) represents an important new resource for benchmarking ADR predictions, explaining novel phenotypic activity and investigating newly discovered clinical properties of marketed drugs.

Item Type:	Article
Keywords:	Adverse drug reactions, adverse event report, FAERS, secondary pharmacology, statistical modeling, drug discovery & development, drug safety
Date Deposited:	01 Sep 2023 00:46
Last Modified:	01 Sep 2023 00:46
URI:	https://oak.novartis.com/id/eprint/48048