In Silico Electrophysiological Analysis Highlights Cardiac Toxicity of Ibrutinib in B-Cell Lymphoma Therapy through Sodium Current Inhibition

Background:
Ibrutinib, a small-molecule drug inhibiting Bruton’s tyrosine kinase, is widely used for treating B-cell lymphoma. However, its potential cardiac toxicity is not fully understood. This study aims to examine how different concentrations of Ibrutinib affect cardiac electrophysiological properties.

Methods:
Using an in-silico electrophysiological model of the sinoatrial node (SAN), we analyzed the effects of Ibrutinib (ranging from 0.1 µmol/L to 10 µmol/L) on the conductance of voltage-gated sodium channels (Nav1.5) over a 200 ms period. Electrophysiological activities were recorded using both current-clamp and voltage-clamp techniques.

Results:
Application of varying current stimuli (0.1-0.10 nA) and durations (10-50 ms) generated action potentials (AP) in the SAN. The current-voltage (I-V) relationship of Nav1.5 under different Ibrutinib concentrations demonstrated a significant reduction in inward current, with a 26% decrease at 10 µmol/L. The I-V curve shifted positively by 20%, and the half-activation potential increased by 28%. This change in inward current was then integrated into a whole-cell model, revealing prolonged AP repolarization and decreased firing frequency at 10 µmol/L Ibrutinib.

Conclusions:
Our findings indicate that high concentrations of Ibrutinib reduce the frequency of spontaneous AP firing by inhibiting Nav1.5 currents, suggesting a risk of cardiac toxicity. Careful dosage management of Ibrutinib is recommended, and further clinical trials are needed to explore its detailed subcellular mechanisms.