Nonclinical safety evaluation of sunitinib: a potent inhibitor of VEGF, PDGF, KIT, FLT3, and RET receptors.
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.
Patyna
Shem
S
Pfizer Global Research and Development, San Diego, California 92121, USA. shem.patyna@pfizer.com
Arrigoni
Claudio
C
Terron
Andrea
A
Kim
Tae-Won
TW
Heward
Joyce K
JK
Vonderfecht
Steven L
SL
Denlinger
Robert
R
Turnquist
Susan E
SE
Evering
Winston
W
D000311:Adrenal Glands / Q000187:drug effects / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D001853:Bone Marrow / Q000187:drug effects / Q000473:pathology; D005260:Female; D041981:Gastrointestinal Tract / Q000187:drug effects / Q000473:pathology; D006132:Growth Plate / Q000187:drug effects / Q000473:pathology; D007180:Incisor / Q000187:drug effects / Q000473:pathology; D007211:Indoles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D008221:Lymphoid Tissue / Q000187:drug effects / Q000473:pathology; D008252:Macaca fascicularis; D008297:Male; D008854:Microscopy, Electron; D009389:Neovascularization, Pathologic / Q000139:chemically induced / Q000473:pathology; D010053:Ovary / Q000187:drug effects / Q000473:pathology; D010179:Pancreas / Q000187:drug effects / Q000473:pathology; D011758:Pyrroles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D020127:Recovery of Function / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D000077210:Sunitinib; D036401:Toxicity Tests, Chronic / Q000379:methods*
D000970:Antineoplastic Agents; D007211:Indoles; D011758:Pyrroles; D020794:Receptor Protein-Tyrosine Kinases; D000077210:Sunitinib