Abstract 14587: Proarrhythmic Effects of Ibrutinib, a Clinically Approved Inhibitor of Bruton’S Tyrosine Kinase (BTK) Used in Cancer Therapy

Abstract

Introduction: Ibrutinib is a novel and potent BTK inhibitor which has been approved for several types of B-cell malignancies. Our meta-analysis of the published clinical trials finds that atrial fibrillation occurs in ~7% of patients after chronic ibrutinib exposure. Ventricular tachycardia has also been reported. Recently, multi-targeted tyrosine kinase inhibitors (TKIs) have been associated with arrhythmias; one implicated mechanism is increased late sodium current (INa-L) after chronic but not acute drug exposure. This effect appears to be mediated by inhibition of PI3Kinase since it is rescued by intra-pipette PIP3, a PI3K effector. Hypothesis: In this study, we tested the hypothesis that chronic exposure to ibrutinib exerts arrhythmogenic effects by this mechanism. Methods: Isolated adult mouse cardiac atrial/ventricular and rabbit ventricular myocytes as well as KCNH2 (HERG/Kv11.1)- or Kv4.3-transfected CHO cells were used for the electrophysiological studies pre- and post-ibrutinib (0.3 μ or 1 μM) acutely (5-10 min) and chronically (5 hrs in myocytes or 48 hrs in CHO cells). In some experiments, 1 μM PIP3 was added into the pipette solution. Results: Chronic but not acute ibrutinib prolonged cardiac action potentials (APs), triggered abnormal APs (EADs and DADs; Figure), and markedly increased cardiac INa-L (1.68±0.27% vs control 0.21±0.04% of peak current, P<0.01) in mouse atrial cells. A similar INa-L increase was also seen in mouse and rabbit ventricular cells. The abnormal APs and increased INa-L were antagonized by adding 1 μM PIP3 into the pipette and by the INa-L blocker ranolazine (10 μM). Ibrutinib has minor and no effects on cardiac HERG and Kv4.3 currents. Conclusion: Ibrutinib, like other TKIs, increased cardiac INa-L, an effect reversed by intracellular PIP3. These data further reinforce the importance of PIP3 signaling as a proximate mechanism leading to arrhythmogenesis by emerging targeted oncology therapies.