Effects of orally administered sunitinib malate (SU11248) on embryo-fetal development in the rat and rabbit

1561 Introduction: Angiogenesis plays a critical role in many physiological processes, including embryo-fetal development. Accordingly, most of the targeted antiangiogenic agents used in oncology are not recommended for use during pregnancy based on existing nonclinical safety data. Sunitinib is an oral, multitargeted RTK inhibitor of VEGFRs, PDGFRs and other RTKs with direct antitumor and antiangiogenic activity. We report the results of three nonclinical studies investigating the effects of orally administered sunitinib on embryo-fetal development in female rats and rabbits. Methods: Sunitinib was administered orally, once daily, to pregnant Sprague-Dawley rats and New Zealand White rabbits for 12 and 14 consecutive days, respectively, during the major period of organogenesis. Sunitinib was administered as a solution in vehicle at doses ranging from 0 (control) to 0.3-30 mg/kg/day in rats, and to 0.5-20 mg/kg/day in rabbits. Body weights, food consumption and clinical observations were recorded throughout gestation. Animals were humanely euthanized and a cesarean section was performed on gestation days 20 or 21 (rats) and 29 (rabbits). Each uterus was weighed intact and a gross necropsy was performed on each female. The numbers of live and dead fetuses, early and late resorptions, corpora lutea and total implantations were recorded. Fetuses were examined grossly (externally), weighed, and euthanized. Rat fetuses were sexed and, in the case of the embryo-fetal development study, were processed for visceral and skeletal examination. Results: Mortality was observed in rats at the highest dose of sunitinib, 30 mg/kg/day. In rats, sunitinib ≥5 mg/kg/day resulted in decreased gravid uterine weights, number of viable fetuses, and fetal body weight, as well as an increased number of resorptions (post-implantation loss), and complete litter loss (in all litters at ≥15 mg/kg/day). Fetal malformations were observed at doses >3 mg/kg/day and consisted primarily of an increased incidence of skeletal malformations, although acephalostomia also occurred in 2 fetuses in the 5 mg/kg/day group. Mortality was observed in rabbits at the highest dose of sunitinib, 20 mg/kg/day, and treatment in this group was terminated early due to overt toxicity and escalating weight loss. At 5 mg/kg/day, reductions in gravid uterine weights and number of live fetuses were due to increases in the number of resorptions (post-implantation loss), and complete litter loss (4 of 6 females). Cleft lip and/or cleft palate were observed at doses ≥1 mg/kg/day. No other treatment-related fetal malformations or variations were observed. Conclusions: As expected for a VEGF signaling inhibitor, sunitinib was associated with embryo-fetal developmental toxicity in female rats and rabbits. These developmental effects were observed at or below the estimated human systemic exposure to sunitinib at 50 mg/day.