Dofetilide – Molecular Pharmacology and Safety Aspects

Introduction: Atrial fibrillation (AF) is the most common sustained arrhythmia globally and a major cause of morbidity and mortality. Its incidence and prevalence are fast increasing due to our rapidly ageing population. Current guidelines recommend the use of class I and III antiarrhythmic agents for rhythm control, both in the acute setting and for long-term management. Dofetilide is an FDA-approved agent for cardioversion and long-term rhythm control in the US. Its known primary target is the hERG channel, which mediates I_Kr in human cardiomyocytes. Yet, few data have been published on dofetilide’s effects on other ion channels, even though this may have important implications for drug safety. This study aims to investigate the effects on ion channels other than hERG to obtain a more complete ion channel inhibition profile for dofetilide. Special emphasis will be placed on the ubiquitously expressed K_2P channel family.

Methods: Two-electrode voltage clamp (TEVC) experiments were used to study the effects of dofetilide on ion channels heterologously expressed in X. laevis oocytes. Cardiac computational simulations were performed to investigate the effect of dofetilide on a virtual AF patient.

Results: TEVC screening using 500 µM dofetilide showed near complete inhibition for hERG (»100%, n=10, p<0.01). At concentrations of 1, 10 and 100 µM dofetilide, we observed 25.3%, 84.4% and 100% inhibition respectively, yielding a calculated IC₅₀ value of 3.2 µM. In addition, we recorded significant inhibition by dofetilide (500 µM) for K_2P18.1 (42.4%, n=7, p=0.0011), K_2P2.1 (34.2%, n=10, p=0.0003), K_2P10.1 (24.2%, n=6, p=0.0007), K_2P9.1 (12.7%, n=8, p=0.0009), as well as K_V4.3 (10.1%, n=6, p=0.038), K_V1.5 (16.1%, n=7, p=0.034) and Na_V1.5 (25.1%, n=8, p=0.0005). No statistically significant effects on K_2P 3.1 (7.5% inhibition, n=12, p=0.053), K_2P1.1 (-4.5%, n=7, p=0.23), K_V1.4 (-11.4%, n=4, p=0.56), K_V2.1 (-6.1%, n=7, p=0.14) and K_ir2.1 (7.3%, n=5, p=0.36) were recorded. Moreover, we observed significant activation of K_2P17.1 (27.6%, n=6, p=0.0007) and K_ir3.1/3.4 (30.6%, n=7, p=0.022). In silico simulations indicated an increased action potential duration and a decreased triangulation of the action potential upon administration of dofetilide. 

Conclusion:
This study screened dofetilide’s effects on the K_2P channel family and other atrially expressed ion channels. Along with strong inhibition of hERG, significant inhibition was found for CNS-expressed K_2P18.1, K_2P2.1, and K_2P10.1. These findings extend the known pharmacological profile of dofetilide and highlight the potential role of extra-cardiac ion channel inhibition in dofetilide-related neurological side effects.