Following a single 600-mg dose of darolutamide, peak levels of darolutamide occur after approximately 4 hours. Steady-state levels of darolutamide occur after 2 to 5 days of continuous administration with food, during which time an approximate 2-fold accumulation in darolutamide levels occurs. At steady state with 600 mg/day darolutamide, mean levels of darolutamide are 4.79 μg/mL and area-under-the-curve levels of darolutamide over time 0 to 12 hours (AUC0–12) are 52.82 h•μg/mL. Total exposure to ketodarolutamide is approximately 1.7-fold that of darolutamide. Distribution
The volume of distribution of darolutamide with intravenous administration is 119 L. The plasma protein binding of darolutamide is 92%, with 8% circulating freely, and of ketodarolutamide is 99.8%, with 0.2% circulating unbound. As such, free levels of darolutamide in the circulation are about 40-fold higher than those of ketodarolutamide. Both darolutamide and ketodarolutamide are bound mainly to albumin. Darolutamide and ketodarolutamide appear to negligibly cross the blood–brain barrier both in mice and humans. Darolutamide is a known substrate of P-glycoprotein and the breast cancer resistance protein (BCRP). P-Glycoprotein is known to play a major role in excluding drugs from the brain due to efflux back across the blood–brain barrier. Metabolism
Darolutamide is primarily metabolized into ketodarolutamide via dehydrogenation by CYP3A4 in the liver. The medication is also conjugated via glucuronidation by UGT1A9 and UGT1A1. The elimination half-life of darolutamide and ketodarolutamide has been reported to be approximately 20 hours.
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.