Electrophysiological Effects of the Anti‐Cancer Drug Lapatinib on Cardiac Repolarization

Abstract

Lapatinib is one of several tyrosine kinase inhibitors used against solid tumour cancers such as breast and lung cancer. Although lapatinib is associated with a risk of QT prolongation, the effects of the drug on cellular cardiac electrical properties and on action potential duration (APD) have not been studied. To evaluate the potential effects of lapatinib on cardiac repolarization, we investigated its electrophysiological effects using a whole-cell patch-clamp technique in transiently transfected HEK293 cells expressing human ether-à-go-go (hERG; to examine the rapidly activating delayed rectifier K + current, I Kr ), KCNQ1 ⁄ KCNE1 (to examine the slowly activating delayed rectifier K + current, I Ks ), KCNJ2 (to examine the inwardly rectifying K + current, I K1 ), or SCN5A (to examine the inward Na + current, I Na ) and in rat cardiac myocytes (to examine the inward Ca 2+ current, I Ca ). We also examined its effects on the APD at 90% (APD 90 ) in isolated rabbit Purkinje fibres. In ion channel studies, lapatinib inhibited the hERG current in a concentration-dependent manner, with a half-maximum inhibition concentration (IC 50 ) of 0.8 € 0.09 lM. In contrast, at concentrations up to 3 lM, lapatinib did not significantly reduce the I Na , I K1 or I Ca amplitudes; at 3 lM, it did slightly inhibit the I Ks amplitude (by 19.4 € 4.7%; p < 0.05). At 5 lM, lapatinib induced prolongation of APD 90 by 16.1% (p < 0.05). These results suggest that the APD 90 -prolonging effect of lapatinib on rabbit Purkinje fibres is primarily a result of inhibition of the hERG current and I Ks , but not I Na , I K1 or I Ca .

Precise safety pharmacology studies of lapatinib for onco-cardiology assessed using in vivo canine models

“…IC 50 values for all other 16 tested enzymes were >1,000-fold higher than for ErbB1/ErbB2 4 . Moreover, lapatinib has been reported to slightly inhibit I Ks at 3,000 nmol/L, but hardly affect the I Na , I Ca and I K1 at this concentration 8 . The IC 25 and IC 50 values of the hERG current were reported to be 181 and 800 nmol/L, respectively 4,8 .…”

“…Moreover, lapatinib has been reported to slightly inhibit I Ks at 3,000 nmol/L, but hardly affect the I Na , I Ca and I K1 at this concentration 8 . The IC 25 and IC 50 values of the hERG current were reported to be 181 and 800 nmol/L, respectively 4,8 . Therefore, the doses of lapatinib used in this study would attain infra-to iso-therapeutic levels of the free plasma concentrations, which can inhibit the ErbB1 and ErbB2 receptors, but , mean blood pressure (MBP), cardiac output (CO), total peripheral vascular resistance (TPR), maximum upstroke velocity of the left ventricular pressure (peak +dP/dt), maximum downstroke velocity of the left ventricular pressure (peak −dP/dt) and left ventricular enddiastolic pressure (LVEDP) after the administration of lapatinib.…”

“…The overall incidence of cardiac adverse events with lapatinib has been reported to be 2.70% (95% confidence interval: 1.60-4.50%), including heart failure in patients with breast cancer and other HER2-positive cancers 7 . Importantly, the drug has been also reported to prolong QT interval in the clinical use 7 and has been shown to inhibit the human ether-à-go-go-related gene (hERG) current in a concentration-dependent manner 8 . However, this potential for QT-interval prolongation has not been indicated in preclinical telemetry studies using dogs 4 .…”

Drug Interactions in Palliative Cancer Care and Oncology

“…It has been well established that absorption is signifi cantly improved with concomitant food, as well as with twice-daily dosing as compared to once-daily dosing Burris et al 2009 ;Devriese et al 2013 ). Lapatinib has also been shown to have a concentration-dependent impact on the QTc, suggesting that agents that increase serum concentrations of lapatinib may also increase the risk of QTc prolongation (Lee et al 2010 ).…”

Use of antineoplastic agents in patients with cancer who have HIV/AIDS

“…Multiple anticancer agents also are associated with QT prolongation including cytotoxic agents and the newer molecularly targeted anticancer agents such as anthracyclines, 92 arsenic trioxide, 92 dasatninb, 93 lapatinib, 94 nilotinib, 95 sunitinib, 96 and tamoxifen. 97 Due to the potential for sudden death, combinations of these agents should be avoided.…”