Visualization of Kinase Inhibition-Related Adverse Events Using the Japanese Adverse Drug Event Report Database

Small molecule tyrosine kinase inhibitors (TKIs) inhibit not only the target kinase but also various kinases as off-target inhibitors not mentioned in the package insert. However, there are no reports that comprehensively examine the relationship between adverse events and kinase affinity.

In this study, we combined basic data and clinical data to visualize the relationship between kinase affinity and adverse events, which will be useful for the management of adverse events in clinical practice.

We targeted TKIs that have been used domestically and for which the dissociation constant was obtained as reported by Davis et al. Adverse event data recorded in the Japanese Adverse Drug Event Report (JADER) database provided by the Pharmaceuticals and Medical Devices Agency between April 2004 and January 2018 were used. We calculated the reporting rates of the Standardized MedDRA Queries (SMQ) for the adverse events of interest and visualized the correlation coefficients with kinase affinity. We used the adverse events associated with VEGFR2 and EGFR to assess their validity.

We found a correlation among known kinase-related adverse events, suggesting that the methodology may be used as a signal detection method to generate hypotheses for clinical and basic research.

Our comprehensive analysis of the kinase affinity of TKIs in this study, which was based on basic TKI kinase affinity data and the clinical data of the reporting rates, suggested that our comprehensive analysis method is useful for generating hypotheses about possible causal relationships between pharmacological effects and adverse events.