Evaluating Sex-Biased Adverse Event-Associated Drugs to Improve Kidney Disease Drug Prioritization

Background: Sex differences impact disease pathology, including kidney diseases (e.g., polycystic kidney disease, PKD; acute kidney injury, AKI). Also, women are more likely to have drug-related adverse events (unintended medication effects), and men are more likely to experience events resulting in hospitalization or death. These sex-biased adverse events (SBAEs) are due to many factors, but it is critical to evaluate the impact of sex when prioritizing drug targets and repurposing candidates. Methods: Previously, we evaluated sex-specific gene expression (GE) of known drug targets and metabolism enzymes for SBAE-associated drugs. We also assessed sex-biased GE and gene-regulatory network properties for 45 tissues to determine if known SBAE-associated drug targets and metabolism enzymes had sex-specific gene properties. We applied these findings to drugs approved for or in clinical trials to treat PKD, AKI, and other kidney diseases. Results: We found ~85% of SBAE-associated targets had sex-biased GE or were core genes of sex- and tissue-specific network communities and demonstrated these data can prioritize drugs for preclinical/clinical kidney disease trials. Conclusion: Our approach may be useful for studies seeking to explain or predict SBAEs, critical for realizing precision medicine for kidney-associated diseases. Funding: Other NIH Support - NIH Office of the Director1. Sex-biased drug-adverse event pairs.2. Sex-biased GE of PKD drug targets.