Impaired embryo cardiac-placental axis at organogenesis associated with dysregulation of VEGF and its receptors after maternal alcohol consumption

Axitinib (Inlyta, Pfizer) is a third-generation selective inhibitor of VEGFR1, VEGFR2, and VEGFR3 receptors, which are involved in normal and tumoral angiogenesis, in the range of IC50 0.06–0.3 nM, while PDGFRs and KIT were inhibited within 1.6 and 5 nM concentrations. In 2012, the Food and Drug Administration (FDA) approved this tyrosine kinase inhibitor for the treatment of advanced renal cell carcinoma (RCC) after failure of one prior systemic therapy. The European Medicines Agency (EMA) approved axitinib in the same year for adult patients with advanced RCC after failure of prior treatment with sunitinib or a cytokine. The initial safety profile of axitinib was assessed through observation of 715 patients in monotherapy, including 537 subjects with RCC, receiving axitinib as second-line treatment. All patients, except those enrolled in the dose escalation investigation, received the recommended dose of 5 mg/bid. The safety profile of axitinib is characterized by gastrointestinal and constitutional disorders, hypertension, mucosal inflammation, dysphonia, and proteinuria, mostly appearing with higher frequency during the first month of treatment. Other significant/concerning events include cardiac failure, gastrointestinal perforation, hemorrhage, and hypothyroidism. Some events, such as glossodynia, hypercalcemia, gastrointestinal perforation, and cardiac failure, were evidenced at later times in clinical trials and postmarketing settings. Overall, these toxicities are within the typical framework of anti-VEGF/VEGFR targeted agents, and in particular of sorafenib, sunitinib, pazopanib, and the monoclonal antibody bevacizumab, with a few differences of relevance.