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Nonclinical Safety Evaluation of Sunitinib: A Potent Inhibitor of VEGF, PDGF, KIT, FLT3, and RET Receptors
1 Pfizer Global Research and Development, San Diego, California, USA Correspondence: Address correspondence to: Shem Patyna, PhD, Oncology Clinical Development, Pfizer Global Research and Development, 10555 Science Center Drive, San Diego, CA 92121, USA; e-mail:shem.patyna{at}pfizer.com. 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.
Key Words: sunitinib malate • receptor tyrosine kinase inhibitor • anti-angiogenesis • nonclinical toxicity Abbreviations: AUC0–24, area under the plasma drug concentration-time curve over a twenty-four-hour dosing interval • , CSF-1Rcolony-stimulating factor receptor • , FGFfibroblast growth factor • , FLT3FMS-like tyrosine kinase-3 receptor • , GIgastrointestinal • , GISTgastrointestinal stromal tumor • , GLPgood laboratory practice • , KITstem cell factor receptor • , NOAELno observed adverse effect level • , OECDOrganization for Economic Cooperation and Development • , PDGFRplatelet-derived growth factor receptor • , RCCrenal cell carcinoma • , RETglial cell-line derived neurotrophic factor receptor (REarranged during Transfection) • , RTKreceptor tyrosine kinase • , VEGFRvascular endothelial growth factor receptor
This version was published on December
1, 2008 Toxicologic Pathology, Vol. 36, No. 7,
905-916 (2008) This article has been cited by other articles:
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