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Sunitinib, a receptor tyrosine kinase inhibitor, increases blood pressure in rats without associated changes in

E Blasi1, J Heyen, S Patyna

  • 1Safety Pharmacology-Pfizer Global Research and Development, La Jolla, CA, USA. eileen.r.blasi@pfizer.com

Cardiovascular Therapeutics
|September 3, 2011
PubMed
Abstract

Insights

Sunitinib increased blood pressure in rats without direct cardiac effects. This multi-tyrosine kinase inhibitor showed no adverse impact on cardiac structure or function in nonclinical studies.

Area of Science:

  • Pharmacology
  • Cardiovascular Toxicology

Background:

  • Sunitinib is a multi-tyrosine kinase inhibitor used for advanced renal cell carcinoma and imatinib-resistant gastrointestinal stromal tumor.
  • Sunitinib is associated with hypertension and other toxicities.

Purpose of the Study:

  • To investigate the direct and indirect effects of sunitinib on cardiac structure and function.
  • To determine if sunitinib-induced hypertension is related to cardiac alterations at clinically relevant exposures.

Main Methods:

  • Nonclinical studies in rats and guinea pigs.
  • Rats received sunitinib (1 or 10 mg/kg/day) or vehicle for 4 weeks, followed by a 2-week off-treatment and 2-week rechallenge.
  • Continuous blood pressure and heart rate monitoring, weekly echocardiograms, and ex vivo evaluation of isolated guinea pig hearts.

Main Results:

  • Sunitinib (10 mg/kg/day) significantly increased blood pressure in rats during dosing and rechallenge, with transient hypotension during the off-treatment period.
  • Heart rate changes were observed, including an increase during the off-treatment period and a decrease during rechallenge.
  • No structural or functional cardiac changes were detected in rats, and neither sunitinib nor its metabolite affected contractility, heart rate, or left ventricular pressure in isolated guinea pig hearts.

Conclusions:

  • Sunitinib and its metabolite have no direct impact on cardiac function.
  • Therapeutically relevant sunitinib concentrations, administered on a clinical schedule, elevate blood pressure in rats without causing adverse cardiac structural or functional changes.

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