Safety Pharmacology-Pfizer Global Research and Development, La Jolla, CA, USA.
Clinical Development- Pfizer Global Research and Development, La Jolla, CA, USA; Drug Safety Biomarkers-Pfizer Global Research and Development, La Jolla, CA, USA; Safety Pharmacology-Pfizer Global Research and Development, Groton, CT, USA.
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.
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.
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).
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.
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.
Written by:
Blasi E, Heyen J, Patyna S, Hemkens M, Ramirez D, John-Baptiste A, Steidl-Nichols J, McHarg A. Are you the author?
Reference: Cardiovasc Ther. 2011 May 31. Epub ahead of print.
doi: 10.1111/j.1755-5922.2011.00278.x
PubMed Abstract
PMID: 21884012
UroToday.com Investigational Urology Section
