As the drug is partly metabolised via the liver enzyme CYP3A4, strong inducers of this enzyme can decrease its blood plasma concentrations. CYP3A4 inhibitors do not significantly increase vandetanib concentrations, presumably because it is also metabolised by flavin containing monooxygenase 1 (FMO1) and 3. Pharmacology
Vandetanib is an inhibitor of vascular endothelial growth factor receptor-2, epidermal growth factor receptor, and RET tyrosine kinases. RET tyrosine kinases; it weakly inhibits VEGFR-3. Vandetanib is well absorbed from the gut, reaches peak blood plasma concentrations 4 to 10 hours after application, and has a half-life of 19 days on average, per pharmacokinetic studies. It has to be taken for about three months to achieve a steady-state concentration. In the blood, it is almost completely (90–96%) bound to plasma proteins such as albumin. It is metabolised to N-desmethylvandetanib via CYP3A4 and to vandetanib-N-oxide via FMO1 and 3. Both of these are active metabolites. Vandetanib is excreted via the faeces (44%) and the urine (25%) in form of the unchanged drug and the metabolites. History
Vandetanib was approved by the FDA in April 2011, for treatment of late-stage thyroid cancer.Vandetanib was first initially marketed without a trade name; it has been marketed under the trade name Caprelsa since August 2011.In 2015 Genzyme acquired the product from AstraZeneca. Research
AstraZeneca tested Vandetanib in clinical trials for non-small cell lung cancer and submitted an application for approval to the EMA but then withdrew the application in October 2009 after trials showed no benefit when the drug was administered alongside chemotherapy.
Renal medullary carcinoma is a rare type of cancer that affects the kidney. It tends to be aggressive, difficult to treat, and is often metastatic at the time of diagnosis. Most individuals with this type of cancer have sickle cell trait or rarely sickle cell disease, suggesting that the sickle cell trait may be a risk factor for this type of cancer. Signs and symptoms
In a case series of 34 patients, Davis and colleagues reported the following signs and symptoms:
macroscopically visible (gross) hematuria (60%)
abdominal or back/flank pain (50%)
significant weight loss (25%)Other researchers have reported a palpable renal mass or enlarged lymph nodes. Causes
The etiology of renal medullary carcinoma is still not completely understood. However, the majority of individuals diagnosed with this type of cancer have had sickle cell trait, in which the person carries one normal copy of the hemoglobin A gene (HbA) and one copy of the hemoglobin A gene harboring the genetic mutation found in sickle cell disease (HbS). These individuals do not have sickle cell disease but can manifest symptoms such as kidney damage over the course of their lives. The other genetic or environmental factors that contribute to the risk of renal medullary carcinoma are unknown. Mechanism
The finding that virtually all people affected by renal medullary carcinoma carry at least one copy of the HbS mutation suggests that sickle cell trait somehow predisposes to this type of cancer. The precise mechanism is unknown, but red blood cells with a sickle cell configuration have been identified in pathology specimens.