Patyna S, Haznedar J, Morris D, Freshwater K, Peng G, Sukbuntherng J, Chmielewski G, Matsumoto D
Pfizer Global Research and Development, San Diego, California 92121, USA.
Birth Defects Res B Dev Reprod Toxicol. 2009 Jun;86(3):204-13. doi: 10.1002/bdrb.20194.
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.
Presumed-pregnant Sprague-Dawley 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.
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 > or =5 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 approximately 5.5- (rats) and approximately 0.3-times (rabbits) the human systemic exposure at the approved sunitinib dose (50 mg/day).
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.
血管生成在胚胎-胎儿发育中起关键作用，基于非临床安全性数据，癌症治疗中使用的大多数靶向血管内皮生长因子（VEGF）的抗血管生成药物在孕期不建议使用。我们研究了舒尼替尼（一种口服的多种受体酪氨酸激酶[RTK]抑制剂，包括VEGF受体）对胚胎-胎儿发育的影响。
假定怀孕的斯普拉格-道利大鼠和新西兰白兔在器官形成的主要时期每天重复口服舒尼替尼（0-30毫克/千克/天）。在整个妊娠期进行临床/体格检查，并采集血样以测定全身暴露量。对所有动物进行尸检（包括子宫检查）并检查胎儿形态。
大鼠母体毒性的未观察到不良反应水平为1-5毫克/千克/天，发育毒性为3毫克/千克/天；兔子分别为1和0.5毫克/千克/天。胚胎-胎儿毒性包括活胎数量减少、吸收和着床后/整窝丢失数量增加；在大鼠剂量≥5毫克/千克/天和兔子剂量5毫克/千克/天时观察到这些情况。畸形包括大鼠的胎儿骨骼畸形（一般为胸/腰椎改变）和兔子的唇腭裂。这些发育影响在舒尼替尼批准剂量（50毫克/天）下的人体全身暴露量的约5.5倍（大鼠）和约0.3倍（兔子）时观察到。
原型单克隆抗体贝伐单抗也有类似的作用报道。正如通常在参与血管生成的RTK强效抑制剂中观察到的那样，舒尼替尼在临床相关剂量水平下与大鼠和兔子的胚胎-胎儿发育毒性相关。
