Sunitinib, a receptor tyrosine kinase inhibitor, increases blood pressure in rats without associated changes in cardiac structure and function

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Abstract

Background: Sunitinib, a multi-tyrosine kinase inhibitor has demonstrated clinical activity in advanced renal cell carcinoma and imatinib-resistant/intolerant gastrointestinal stromal tumor. It has been associated with manageable hypertension and other unique toxicities. Aims: Two nonclinical studies were conducted to determine if sunitinib has direct/indirect effects on cardiac structure/function that may be related to hypertension at clinically relevant exposures. Materials & Methods: Rats received once-daily vehicle or sunitinib 1 or 10 mg/kg/day (n = 10/group) orally for 4 weeks, followed by 2 weeks off treatment then a 2-week rechallenge. Blood pressure (BP) and heart rate (HR) were continuously acquired and echocardiograms were obtained weekly. Effects of sunitinib and its metabolite (0.003-0.3 μM) were also evaluated in guinea pig isolated Langendorff-perfused hearts (n = 4-6 hearts/group). Results: Sunitinib 10 mg/kg/day produced significant (P < 0.05) hemodynamic changes: 24 h average BP increased during initial dosing/rechallenge, with rebound hypotension during the off-treatment period; 24 h average HR increased during the off-treatment period, and decreased during rechallenge; no changes in cardiac structure/function were observed. In guinea pig isolated hearts, neither sunitinib nor its metabolite had direct effects on contractility, HR or left ventricular pressure. Discussion & Conclusion: These studies demonstrate that sunitinib/metabolite had no direct effects on cardiac function ex vivo, and that therapeutically relevant concentrations of sunitinib dosed on a "clinical schedule" increased BP in rats without adverse changes in cardiac structure/function. © 2011 Blackwell Publishing Ltd.

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Blasi, E., Heyen, J., Patyna, S., Hemkens, M., Ramirez, D., John-Baptiste, A., … Mcharg, A. (2012). Sunitinib, a receptor tyrosine kinase inhibitor, increases blood pressure in rats without associated changes in cardiac structure and function. Cardiovascular Therapeutics, 30(5), 287–294. https://doi.org/10.1111/j.1755-5922.2011.00278.x

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