Abstract
Atrial fibrillation is a side effect of ibrutinib, an irreversible inhibitor of Bruton
tyrosine kinase used for treatment of B-cell lymphoproliferative disorders. We determined
if single (2 or 10 mg/kg), or chronic (14 days) oral ibrutinib followed by 24-hour
washout conferred susceptibility to electrically induced arrhythmias in 1-month-old
male C57BL/6 mice. A single higher dose of ibrutinib increased arrhythmia inducibility.
There was no inducibility difference after chronic dosing with washout. This suggests
that high serum drug levels might be responsible for the proarrhythmic effect of ibrutinib
and that an altered dosing strategy might mitigate the side effects.
Résumé
La fibrillation auriculaire est un effet secondaire de l’ibrutinib, un inhibiteur
irréversible de la tyrosine kinase de Bruton servant au traitement des troubles lymphoprolifératifs
à cellules B. Nous avons évalué si l’administration d’ibrutinib par voie orale en
une dose unique (2 ou 10 mg/kg) ou en continu (14 jours) suivie d’une période de sevrage
de 24 heures conférait une susceptibilité à l’arythmie électro-induite chez des souris
mâles C57BL/6 âgées de 1 mois. Une dose unique plus élevée d’ibrutinib a accru l’inductibilité
de l’arythmie. Après l’administration en continu suivie d’une période de sevrage,
aucune différence n’a été observée quant à l’inductibilité. Ces résultats laissent
croire que des concentrations sériques élevées du médicament pourraient expliquer
l’effet proarythmique de l’ibrutinib et qu’une stratégie de modification de la posologie
pourrait atténuer ses effets secondaires.
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Canadian Journal of CardiologyAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy.Proc Natl Acad Sci U S A. 2010; 107: 13075-13080
- Bruton tyrosine kinase represents a promising therapeutic target for treatment of chronic lymphocytic leukemia and is effectively targeted by PCI-32765.Blood. 2011; 117: 6287-6296
- The Bruton tyrosine kinase inhibitor PCI-32765 ameliorates autoimmune arthritis by inhibition of multiple effector cells.Arthritis Res Ther. 2011; 13: R115
- The risk of atrial fibrillation with ibrutinib use: a systematic review and meta-analysis.Blood. 2016; 128: 138-140
- Screening for atrial fibrillation in 13 122 Hong Kong citizens with smartphone electrocardiogram.Heart. 2017; 103: 24-31
- Ibrutinib increases the risk of atrial fibrillation, potentially through inhibition of cardiac PI3K-Akt signaling.Blood. 2014; 124: 3829-3830
- Ibrutinib, an approved tyrosine kinase inhibitor as a potential cause of recurrent polymorphic ventricular tachycardia.J Am Coll Cardiol Clin Electrophysiol. 2016; 2: 847-849
- Ventricular arrhythmias and sudden death in patients taking ibrutinib.Blood. 2017; 129: 2581-2584
- Inhibition of BTK and ITK with ibrutinib is effective in the prevention of chronic graft-versus-host disease in mice.PLoS One. 2015; 10: e0137641
- Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed/refractory B-cell malignancies.J Clin Oncol. 2013; 31: 88-94
- Evidence for enhanced M3 muscarinic receptor function and sensitivity to atrial arrhythmia in the RGS2-deficient mouse.Am J Physiol Heart Circ Physiol. 2010; 298: H554-H561
- Atrial tachycardia/fibrillation in the connexin 43 G60S mutant (oculodentodigital dysplasia) mouse.Am J Physiol Heart Circ Physiol. 2011; 300: H1402-H1411
- Remodelling of gap junctions and connexin expression in diseased myocardium.Cardiovasc Res. 2008; 80: 9-19
- Connexins and atrial fibrillation: filling in the gaps.Circulation. 2012; 125: 203-206
- Multicolor and electron microscopic imaging of connexin trafficking.Science. 2002; 296: 503-507
- Dephosphorylation and intracellular redistribution of ventricular connexin43 during electrical uncoupling induced by ischemia.Circ Res. 2000; 87: 656-662
- Atrial fibrillation as a complication of ibrutinib therapy: clinical features and challenges of management.Leuk Lymphoma. 2018; 59: 311-320
Article info
Publication history
Published online: December 07, 2017
Accepted:
December 1,
2017
Received:
July 13,
2017
Footnotes
See page 340 for disclosure information.
Identification
Copyright
© 2017 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.
