Reproductive Toxicity Assessment of Sunitinib, A Multitargeted Receptor Tyrosine Kinase Inhibitor, in Male and Female Rats

• Published in: Birth defects research. Part B. Developmental and reproductive toxicology 2012-08, Vol.95 (4), p.267-275
• Main Authors: Coburn, Aleasha M., Cappon, Gregg D., Bowman, Christopher J., Stedman, Donald B., Patyna, Shem
• Format: Article
• Language: English
• Subjects: Animals; antiangiogenesis; Body Weight - drug effects; Embryonic Development - drug effects; Epididymis - anatomy & histology; Epididymis - drug effects; Estrous Cycle - drug effects; Female; Females; Fertility; Fertility - drug effects; Indoles - toxicity; Male; Males; Organ Size - drug effects; PDGFR inhibitor; Pregnancy; Protein Kinase Inhibitors - toxicity; Proteins; Pyrroles - toxicity; rat; Rats; Rats, Sprague-Dawley; Receptor Protein-Tyrosine Kinases - antagonists & inhibitors; receptor tyrosine kinase inhibitor; Reproduction - drug effects; Rodents; Spermatozoa - drug effects; Spermatozoa - metabolism; sunitinib; Testis - anatomy & histology; Testis - drug effects; Toxicity; Toxicity Tests - methods; VEGFR inhibitor
• ISSN: 1542-9733; 1542-9741
• DOI: 10.1002/bdrb.21012

BACKGROUND Sunitinib (SUTENT, Pfizer Inc., New York, NY) is a multitargeted inhibitor of selected receptor tyrosine kinases, which produces an antiproliferative and antiangiogenic effect by blocking pathways fundamental to tumor growth and survival. We investigated the effects of sunitinib on male and female fertility and early embryonic development in the rat. METHODS In the female fertility and early embryonic development phase, untreated males were paired with treated females dosed at 0 (control), 0.5, 1.5, and 5 mg/kg/day from 14 days premating, through mating, to gestation day 7. In the male fertility phase, the same males were then treated 58 days at doses of 0 (control), 1, 3, and 10 mg/kg/day, mated with untreated females, with continued daily dosing for a total of 74 days. RESULTS There was no systemic toxicity‐ or treatment‐related effects on fertility in female rats. Females exposed at 5 mg/kg/day had an increase in the number of early resorptions with associated decrease in viable embryos. In the males, body weight and food consumption were decreased at 10 mg/kg/day compared to the controls. Male reproductive capacity, as assessed by copulation, fertility, and conception indices, was not impacted at any dose level. Sperm morphology, concentration, and motility were also unaffected by treatment. CONCLUSIONS There were no effects on male reproduction. An increase in corpora lutea and an increase in early resorptions with associated reduction in viable embryos was noted in the females dosed 5 mg/kg/day. Sunitinib at doses up to 1.5 and 10 mg/kg/day had no effects on female and male reproduction, respectively.