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.
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.
Authors: Prashant B Nigade; Jayasagar Gundu; K Sreedhara Pai; Kumar V S Nemmani Journal: Eur J Drug Metab Pharmacokinet Date: 2017-10 Impact factor: 2.441
Authors: M Skinner; K Philp; D Lengel; L Coverley; E Lamm Bergström; P Glaves; H Musgrove; H Prior; M Braddock; R Huby; J O Curwen; P Duffy; A R Harmer Journal: Br J Pharmacol Date: 2014-05 Impact factor: 8.739
Authors: Nancy S Saad; Kyle Floyd; Amany A E Ahmed; Peter J Mohler; Paul M L Janssen; Mohammad T Elnakish Journal: PLoS One Date: 2016-04-15 Impact factor: 3.240
Authors: Alice C O'Farrell; Rhys Evans; Johanna M U Silvola; Ian S Miller; Emer Conroy; Suzanne Hector; Maurice Cary; David W Murray; Monika A Jarzabek; Ashwini Maratha; Marina Alamanou; Girish Mallya Udupi; Liam Shiels; Celine Pallaud; Antti Saraste; Heidi Liljenbäck; Matti Jauhiainen; Vesa Oikonen; Axel Ducret; Paul Cutler; Fionnuala M McAuliffe; Jacques A Rousseau; Roger Lecomte; Suzanne Gascon; Zoltan Arany; Bonnie Ky; Thomas Force; Juhani Knuuti; William M Gallagher; Anne Roivainen; Annette T Byrne Journal: PLoS One Date: 2017-01-27 Impact factor: 3.240