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Published on: January 21, 2018
PI3K/mTOR inhibitor omipalisib prolongs cardiac repolarization along with a mild proarrhythmic outcome in the AV
J J A van Bavel1, C Pham1, H D M Beekman1
1Division of Heart and Lungs, Department of Medical Physiology, University Medical Center Utrecht, Utrecht, Netherlands.
Background:
The phosphoinositide 3-kinase (PI3K) signaling pathway is an interesting target in cancer treatment. The awareness of the proarrhythmic risk of PI3K inhibitors was raised because PI3K is also involved in regulating signaling toward cardiac ion channels. Canine cardiomyocytes treated with PI3K inhibitors show an increased action potential duration and reduced cardiac repolarizing currents. Now, the potential proarrhythmic effect of chronic treatment of PI3K/mTOR inhibitor GSK2126458 (omipalisib) was investigated in the atrioventricular (AV) block dog model.
Methods:
Purpose-bred Mongrel dogs received complete AV block by ablation of the bundle of His and their hearts were paced in the right ventricular apex at VDD-mode (RVA-VDD). In this way, sinus rhythm was maintained for 15 ± 1 days and thereby bradycardia-induced cardiac remodeling was prevented. Dogs received 1 mg/kg omipalisib once (n = 3) or twice (n = 10) a day via oral administration for 7 days. Under standardized conditions (anesthesia, bradycardia at 60 beats/min, and a dofetilide challenge), potential proarrhythmic effects of omipalisib were investigated.
Results:
Twice daily dosing of omipalisib increased accumulative plasma levels compared to once daily dosing accompanied with adverse events. Omipalisib prolonged the QT interval at baseline and more strongly after the dofetilide challenge (490 ± 37 to 607 ± 48 ms). The arrhythmic outcome after omipalisib resulted in single ectopic beats in 30% of dogs perpetuating in multiple ectopic beats and TdP arrhythmia in 20% of dogs. Isolated ventricular cardiomyocytes from omipalisib-treated dogs showed a diminished IKs current density.
Conclusion:
Chronic treatment of PI3K/mTOR inhibitor omipalisib prolonged the QT interval in a preclinical model under standardized proarrhythmic conditions. Furthermore, this study showed that electrical remodeling induced by omipalisib had a mild proarrhythmic outcome.
Insights
The PI3K/mTOR inhibitor omipalisib prolonged the QT interval and caused mild proarrhythmic effects in dogs. This highlights the cardiac risks associated with PI3K inhibitors, impacting cancer treatment considerations.
Area of Science:
- Cardiovascular pharmacology
- Oncology drug development
- Cardiac electrophysiology
Background:
- The phosphoinositide 3-kinase (PI3K) pathway is a cancer treatment target.
- PI3K inhibitors carry proarrhythmic risks due to their effects on cardiac ion channels.
- Previous studies showed PI3K inhibitors increase action potential duration and reduce repolarizing currents in cardiomyocytes.
Purpose of the Study:
- To investigate the proarrhythmic effects of chronic PI3K/mTOR inhibitor GSK2126458 (omipalisib) treatment.
- To assess omipalisib's impact on cardiac electrophysiology in a preclinical AV block dog model.
Main Methods:
- Complete atrioventricular (AV) block was induced in purpose-bred Mongrel dogs.
- Dogs were orally administered omipalisib once or twice daily for 7 days.
- Proarrhythmic effects were evaluated under standardized conditions, including anesthesia, bradycardia, and dofetilide challenge.
Main Results:
- Twice daily omipalisib dosing led to higher plasma levels and adverse events.
- Omipalisib significantly prolonged the QT interval, especially after dofetilide challenge (from 490 ± 37 to 607 ± 48 ms).
- Treatment resulted in ectopic beats (30%) and Torsades de Pointes arrhythmia (20%), with diminished IKs current density in cardiomyocytes.
Conclusions:
- Chronic omipalisib treatment prolonged the QT interval in a preclinical model.
- Electrical remodeling induced by omipalisib demonstrated mild proarrhythmic outcomes.
- Findings emphasize the need to consider cardiac safety during PI3K inhibitor development for cancer therapy.
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