Evaluation of the safety and pharmacokinetics of the multi-targeted receptor tyrosine kinase inhibitor sunitinib during embryo–fetal development in rats and rabbits

BACKGROUND: Angiogenesis plays a key role in embryo–fetal development and, based on nonclinical safety data, the majority of vascular endothelial growth factor (VEGF)-targeted antiangiogenic agents used in cancer therapy are not recommended during pregnancy. We investigated the effects of sunitinib (an oral inhibitor of multiple receptor tyrosine kinases [RTKs] including VEGF-receptors) on embryo–fetal development. METHODS: Presumed-pregnant SpragueDawley rats and New Zealand White rabbits received repeated daily oral doses of sunitinib (0–30mg/kg/day), during the major period of organogenesis. Clinical/physical examinations were performed throughout the gestation phase, and blood samples were collected to determine systemic exposure. Necropsy (including uterine examination) was performed on all animals and fetal morphology was examined. RESULTS: The no-observed-adverse-effect level was 1–5mg/kg/ day for maternal toxicity and 3mg/kg/day for developmental toxicity in rats; 1 and 0.5mg/kg/day, respectively, in rabbits. Embryo–fetal toxicity included decreases in the number of live fetuses and increases in the numbers of resorptions and post-implantation/complete litter losses; these were observed at doses of Z5mg/kg/day in rats and 5mg/kg/day in rabbits. Malformations included fetal skeletal malformations (generally thoracic/lumbar vertebral alterations) in rats and cleft lip/palate in rabbits. These developmental effects were observed at B5.5- (rats) and B0.3times (rabbits) the human systemic exposure at the approved sunitinib dose (50mg/day). CONCLUSIONS: Similar effects have been reported with the prototype monoclonal antibody bevacizumab. As is typically observed for potent inhibitors of RTKs involved in angiogenesis, sunitinib was associated with embryo–fetal developmental toxicity in rats and rabbits at clinically relevant dose levels. Birth Defects Res (Part B) 86:204–213, 2009. r 2009 Wiley-Liss, Inc.