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

Abstract

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 (0-30 mg/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 1-5 mg/kg/ day for maternal toxicity and 3 mg/kg/day for developmental toxicity in rats; 1 and 0.5 mg/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 Z5 mg/kg/day in rats and 5 mg/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 B0.3-times (rabbits) the human systemic exposure at the approved sunitinib dose (50 mg/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.

Use of erlotinib throughout pregnancy: A case-report of a patient with metastatic lung adenocarcinoma

“…Studies on rats and rabbits have evidenced that tyrosine kinase inhibitors alter placental angiogenesis, which is associated with toxicity for embryonic development, placental hemorrhage, visceral, neurologic and skeletal malformations, intrauterine growth restriction and fetal death [10,11]. Erlotinib has been reported as the cause of embryonic and fetal death in rabbits when administered at a dose that achieved plasma concentrations approximately 3 times higher than those used in humans.…”

Safe handling of oral antineoplastic medications: Focus on targeted therapeutics in the home setting

“…80,81 In a recent animal study sunitinib, a potent oral multi-targeted TKI exhibited antitumour and antiangiogenic activities, was associated with embryo–foetal toxicity and malformations such as thoracic/ lumbar vertebral alterations in rats and cleft lip/palate in rabbits at clinically relevant dose levels. 82 The observed embryo-toxic effects and skeletal abnormalities associated with sunitinib suggest the predictive critical role of vascular endothelial growth factor (VEGF)-mediated angiogenesis in embryo–foetal development, including endochondral bone formation.…”

Treatment of cancer during pregnancy with monoclonal antibodies: a real challenge

“…The administration of bevacizumab in pregnant mice resulted in disruption of survival of the pre-existing luteal blood vessels in the ovary and termination of embryonic development [26], in addition to several developmental anomalies [18,20]. This was also observed with sunitinib, which is a small-molecule tyrosine kinase inhibitor targeting several angiogenesis-related proteins [27].…”