Cardiovascular effects in rats following exposure to a receptor tyrosine kinase inhibitor.

The receptor tyrosine kinase receptor (RTK) signaling pathway, mesenchymal-epithelial transition factor (c-Met)/hepatocyte growth factor receptor (HGFR), has been implicated in oncogenesis and is a target of interest in cancer therapy. PF-04254644 is a potent and selective inhibitor of c-Met/HGFR. Wide ligand binding profiling of PF-04254644 revealed a potentially significant interaction with phosphodiesterase (PDE) 3, and follow-up PDE enzyme activity assays confirmed PF-04254644 as a potent inhibitor of PDE3 as well as other PDEs (1, 2, 5, 10, and 11). Clinical observations, laboratory, and echocardiography parameters were recorded in Sprague-Dawley (SD) rats that received PF-04254644 oral dosing for up to seven consecutive days. Toxicological evaluations revealed myocardial degeneration as an adverse event at all tested doses. Echocardiographic evaluations revealed an increase in heart rate (HR) and contractility after the first dose with PF-04254644 and myocardial fibrosis correlated with decreased cardiac function after repeat dosing. A study in telemetry-instrumented rats substantiated that PF-04254644 induced a sustained increased HR and decreased contractility after six days of treatment. Data suggest that the decreased cardiac function and cardiotoxicity are likely due to inhibition of multiple PDEs by PF-04254644.