The interplay between molecular architecture, pharmacology, and suspected adverse drug reactions associated with nonsteroidal androgen antagonists in the United Kingdom

Br J Clin Pharmacol. 2026 Apr 29. doi: 10.1002/bcp.70569. Online ahead of print.

ABSTRACT

AIMS: This work aimed to correlate potential links between the suspected adverse drug reaction (ADR) profile of licensed nonsteroidal androgen receptor antagonists (NSARA) with their unique chemical properties and known off-target polypharmacology.

METHODS: Physicochemical and polypharmacology data were curated from the Electronic Medicines Compendium, FDA New Drug Applications documents, and ChEMBL database. Suspected ADRs and fatalities were curated from the United Kingdom Medicines and Healthcare products Regulatory Authority (MHRA) Yellow card spontaneous reporting scheme. The number of daily doses (dd) was extrapolated from OpenPrescribing and NHS Digital secondary care medicines data.

RESULTS: A total of n = 2522 suspected ADRs were associated with 42 903 000 dd of NSARAs usage in the United Kingdom. The highest number of ADRs were associated with enzalutamide (n = 1091) and bicalutamide (n = 738). Enzalutamide was found to have the most off-target pharmacological interactions of the NSARAs studied (n = 4) including potent inhibition of γ-aminobutyric acid, GABA receptor (IC50 = 2.6 μM vs. Cmax = 7.7 μM and Cmax, unbound = 185-212 nM) associated with nervous system disorders (n = 72, accounting for 67% of all NSARA ADRs in this SOC).

CONCLUSIONS: Suspected skin and subcutaneous ADRs approached statistical significance and were interrogated for chemical and pharmacological connections for the first time with the aid of matched molecular pair (MMP) analysis. A potential correlation to nervous system disorders and cardiac arrhythmia for the GABA and hERG inhibitors, enzalutamide and apalutamide, respectively was identified. Darolutamide’s interaction with the 5-HT (SERT) transporter may influence ADRs associated with cardiac and hepatobiliary SOCs.

PMID:42057435 | DOI:10.1002/bcp.70569