508 - Electrophysiological investigation of the effects of metoprolol and diltiazem on pazopanib induced prolonged cardiac repolarisation and proarrythmic...

Date 28 September 2012
Event ESMO Congress 2012
Session Publication Only
Topics Complications of Treatment
Presenter Tulay Akman
Authors T. Akman1, O. Erbas2, L. Akman3, A.U. Yilmaz4
  • 1DOKUZ EYLUL UNIVERSITY FACULTY OF MEDICINE, IZMIR/TR
  • 2Department Of Physiology, Ege University Medical School, Izmir/TR
  • 3Department Of Obstetrics And Gynecology, Ege University Medical School, Izmir/TR
  • 4Medical Oncology, DOKUZ EYLUL UNIVERSITY FACULTY OF MEDICINE, IZMIR/TR

Abstract

Objective

Pazopanib is a potent multi-targeted tyrosine kinase inhibitor which is approved for the treatment of advanced RCC patients. While exploring the therapeutic index of TKIs, oncology investigators are confronted with drug adverse effects such as cardiac toxicities. QT prolongation has taken attention because of the risk of serious cardiac arrhythmias such as torsade de pointes (TdP) and sudden cardiac death. In several studies QTc prolongation was observed with TKIs such as sunitinib, vandetanib, dasatinib, crizotinib. However there are no data showing QTc prolongation with pazopanib treatment. In this study, we aimed to demonstrate the pazopanib induced proarrythmic electrophysiological effects and investigate the possible protective effects of metoprolol and diltiazem to ECG changes in an experimental model.

Method

In this study 24 Sprague-Dawley adult male rats were used. Rats were randomly assigned to 4 groups (n = 6). To the first group (normal group), intraperitoneal injection of 6 ml/kg of saline were given and to the other groups 100 mg/kg pazopanib were given via orogastric tubes. 3 hours after oral administration of pazopanib, to the second group (control group) saline, to the third group 1 mg/kg metoprolol and to the fourth group 1mg/kg diltiazem were applicated intraperitoneally. 1 hours after application of these drugs, under anesthesia, QTc was calculated by taking ECG in derivation I.

Results

The mean QTc interval was 126,2 ± 2.99 s in group 1, 159.66 ± 6.02 s in group 2, 106.66 ± 2.64 in group 3 and 123.33 ± 1.72 s in group 4. Groups 3 and 4 had significantly shorter QTc intervals compared to group 2 (p < 0.001).

Conclusion

This is the first experimental study evaluating the use of prophylactic therapy with metoprolol and diltiazem in pazopanib induced QT prolongation. In this present experimental study we demonstrated the beneficial prophylactic effects of metoprolol and diltiazem in pazopanib induced QT prolongation. More evidence is needed to evaluate the effectiveness and safety of these drugs. Future prospective and randomized studies will be needed to confirm recommendations for high risk patients.

Disclosure

All authors have declared no conflicts of interest.