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 halothaneanaesthetised 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.

Lapatinib antitumor effect is associated with PI3K and MAPK pathway: An analysis in human and canine prostate cancer cells

“…The characterization of dogs as a model for human PC has provided valuable information regarding tumor biology and antitumor response [ 26 , 27 ]. The pharmacologic mechanisms and antitumor response of lapatinib could be explored and understood better using dogs as cancer models [ 28 , 29 ]. Dogs with advanced stage bladder cancer were treated with lapatinib as first-line treatment, showing a high response rate [ 30 ].…”

Comparative pharmacokinetics of tyrosine kinase inhibitor, lapatinib, in dogs and cats following single oral administration

“…Although lapatinib treatment has been frequently used in human breast tumors and canine bladder tumor therapy, its use in cats has been limited due to the absence of pharmacokinetic data [ 11 , 23 ]. On the other hand, the safety reports of lapatinib in dogs have been published in some literatures [ 1 , 22 ]; however, there is no complete pharmacokinetic profile to be evaluated as we know. The main purpose of the present study is to determine the pharmacokinetic characteristics of lapatinib in dogs and cats following single oral administration and evaluate the differences between these two species.…”