Abstract 2221 In silico electrophysiological study reveals Ibrutinib, an important therapeutic agent for B-Cell lymphoma causes cardiac toxicity by inhibiting sodium current

Background: Ibrutinib is a small-molecule drug that acts as an irreversible inhibitor of Bruton's tyrosine kinase and is used as an important therapeutic agent for B-cell lymphoma. Accumulated clinical and experimental evidence supports that Ibrutinib causes sinus bradycardia, which influences the quality of life. Cardiotoxicity due to the use of Ibrutinib is still under clinical investigation. The purpose of this study is to clarify the propensity of Ibrutinib concentration in modulating cardiac electrophysiological properties. Methods: The electrophysiological setup of the sinoatrial node (SAN) comprises the inward rectifier ion channels, voltage-gated sodium channel, voltage-gated potassium channel, L-type calcium channel, calcium-dependent potassium channel, funny current channel, and calcium diffusion mechanisms. Concentration-dependent Ibrutinib (0.1 μmol/L to 10 μmol/L) profile for 200 ms is induced to alter the conductance of voltage-gated sodium ion channel (Nav1.5) and then incorporated into the SA node electrophysiology. Both current-clamp and voltage-clamp protocols are applied to record the electrophysiological activities. Results: After injecting a current stimulus (Istim) of varying magnitude (0.1-0.10 nA) and duration (10-50 ms), action potentials (AP) are reproduced by the SA node. The modulating effects of Ibrutinib concentration on the SA node's electrophysiological properties are investigated in two folds. First, we reproduced the current-voltage (I-V) curve profile of the Nav1.5 ion channel with respect to multiple doses of Ibrutinib under the voltage clamp protocol. It showed the continuous decrease of inward current because of multiple doses of Ibrutinib. At the highest concentrations (10 μmol/L), the peak of the inward current reduced to 26% of its' control value. The I-V curve is shifted to a 20% more positive side and the half-activation potential is increased by 28%. Then, the altered inward current is incorporated into the whole-cell model to investigate the AP firing patterns. For 10 μmol/L of Ibrutinib, the repolarization phase of AP was prolonged and the frequency of the firing pattern was reduced. Conclusions: Our study suggests that Ibrutinib at a higher concentration reduces the frequency rate of the spontaneous AP firing by suppressing the Nav1.5 current. Therefore, the dosage of Ibrutinib should be controlled to avoid cardiac toxicity. Further clinical trials are essential to analyze its' subcellular mechanisms.