Nonclinical safety evaluation of sunitinib: a potent inhibitor of VEGF, PDGF, KIT, FLT3, and RET receptors

• Published in: Toxicologic pathology Vol. 36; no. 7; p. 905
• Main Authors: Patyna, Shem, Arrigoni, Claudio, Terron, Andrea, Kim, Tae-Won, Heward, Joyce K, Vonderfecht, Steven L, Denlinger, Robert, Turnquist, Susan E, Evering, Winston
• Format: Journal Article
• Language: English
• Published: United States 01.12.2008
• Subjects: Adrenal Glands - drug effects; Adrenal Glands - pathology; Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - toxicity; Bone Marrow - drug effects; Bone Marrow - pathology; Female; Gastrointestinal Tract - drug effects; Gastrointestinal Tract - pathology; Growth Plate - drug effects; Growth Plate - pathology; Incisor - drug effects; Incisor - pathology; Indoles - administration & dosage; Indoles - pharmacokinetics; Indoles - toxicity; Lymphoid Tissue - drug effects; Lymphoid Tissue - pathology; Macaca fascicularis; Male; Microscopy, Electron; Neovascularization, Pathologic - chemically induced; Neovascularization, Pathologic - pathology; Ovary - drug effects; Ovary - pathology; Pancreas - drug effects; Pancreas - pathology; Pyrroles - administration & dosage; Pyrroles - pharmacokinetics; Pyrroles - toxicity; Rats; Rats, Sprague-Dawley; Receptor Protein-Tyrosine Kinases - antagonists & inhibitors; Recovery of Function - drug effects; Signal Transduction - drug effects; Toxicity Tests, Chronic - methods
• DOI: 10.1177/0192623308326151

Sunitinib malate (SUTENT) is a multitargeted receptor tyrosine kinase (RTK) inhibitor that is approved multinationally for the treatment of imatinib-resistant/-intolerant gastrointestinal stromal tumor and advanced renal cell carcinoma. This paper characterizes the organ toxicity of sunitinib in Sprague-Dawley rats and cynomolgus monkeys, and the reversibility of any treatment-induced effects. Rats and monkeys received sunitinib (0-15 and 0-20 mg/kg/day, respectively) orally on a consecutive daily dosing schedule for thirteen weeks or on an intermittent daily dosing schedule for up to nine months. Clinical observations and laboratory parameters were recorded. Necropsy was conducted following treatment/recovery periods, and histologic examinations were performed. In rats, sunitinib was generally tolerated at 0.3 and 1.5 mg/kg/day, and findings were reversible. In monkeys, the level at which there were no observed adverse effects was 1.5 mg/kg/day, and findings were similarly reversible (except for uterine/ovarian weight changes and skin pallor). Data suggest that inhibition of multiple RTK pathways may induce pharmacologic effects on organ systems in nonclinical species. Key pharmacologic effects of sunitinib included reversible inhibition of neovascularization into the epiphyseal growth plate, and impaired corpora lutea formation and uterine development during estrus. Similar observations have been noted with this class of RTK signaling inhibitors and are consistent with pharmacologic perturbations of physiologic/angiogenic processes associated with the intended molecular targets.