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

Abstract

Cancer chemotherapies have improved prognosis in cancer patients, resulting in a large and rapidly increasing number of cancer survivors. "Onco-cardiology" or "cardio-oncology" is a new discipline for addressing the unanticipated cardiac side effects of newly developed cancer drugs. Lapatinib, a tyrosine kinase inhibitor suppressing the epidermal growth factor receptor and ErbB2, has been used in advanced or metastatic breast cancer treatment. Reportedly, lapatinib has induced cardiovascular adverse events including QT-interval prolongation and heart failure. However, they have not been predicted by preclinical studies. Hence, a new method to assess the tyrosine kinase inhibitor-induced adverse effects needs to be established. Here, we intravenously administered lapatinib to halothane-anaesthetised dogs, evaluating cardiohemodynamic, electrophysiological, and echocardiographic profiles for pharmacological safety assessments. We intravenously administered lapatinib to chronic atrioventricular block beagle dogs to assess its proarrhythmic potential. The therapeutic concentration of lapatinib significantly increased total peripheral vascular resistance, QT, QTc, monophasic action potential (MAP)_90(sinus), MAP_90(CL400), effective refractory period, and plasma concentration of cardiac troponin I (cTnI), suggesting that lapatinib prolonged the ventricular repolarization without inducing lethal ventricular arrhythmia. Careful monitoring of plasma cTnI concentration and an electrocardiogram could be supportive biomarkers, predicting the onset of lapatinib-induced cardiovascular adverse events.

Figure 1

Time courses of change in the heart rate (HR), 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 end-diastolic pressure (LVEDP) after the administration of lapatinib. Data are presented as mean ± SEM (n = 5). Closed symbols represent significant differences from the corresponding pre-drug basal control values (C) by p < 0.05.

Figure 2

Time courses of changes in the PR interval (circles), QRS width (triangles), QT interval (squares) and QTcV (squares), atrio-His interval (AH; circles), His-ventricular interval (HV; triangles); the MAP₉₀ at sinus rhythm, pacing cycle length of 400 ms (MAP_90(CL400)) and 300 ms (MAP_90(CL300)); the effective refractory period of the right ventricle (ERP) and terminal repolarization period (TRP) after the administration of lapatinib. QT interval was corrected with Van de Water’s formula. Data are presented as mean ± SEM (n = 5). Closed symbols represent significant differences from the corresponding pre-drug basal control values (C) by p < 0.05. MAP₉₀: monophasic action potential duration at 90% repolarization level.

Figure 3

The time courses of the plasma concentrations of lapatinib, cardiac troponin I (cTnI), NT-proBNP, creatinine kinase (CK; circles), aspartate aminotransferase (AST; triangles) and lactate dehydrogenase (LDH; circles). Number of data in cTnI, CK, AST and LDH was 5 besides NT-proBNP. Number of data in NT-proBNP was 3, as the remaining 2 were the lower limit of quantitation during the experiment. Data are presented as mean ± SEM (n = 5). Closed symbols represent significant differences from the corresponding pre-drug basal control values (C) by p < 0.05.

Figure 4

Time courses of changes in the ventricular rate, QT interval, and QTcF after the 3 mg/kg of intravenous administration of lapatinib in the chronic atrioventricular block dogs. Data are presented as mean ± SEM (n = 4).

Figure 5

Poincaré plots of the QT interval obtained in each chronic atrioventricular block animal. A total of 31 beats were plotted for each of the two-analysis time-points; namely, before (Pre, black), and 1(blue) and 21 h (red) after the 3 mg/kg of intravenous administration of lapatinib. STV, short-term variability; LTV, long-term variability.