ministration are available in two dosage strengths, 100 mg and 300 mg, containing 100 mg and 300 mg of Vandetanib, respectively. The tablet cores contain the following inactive ingredients: Tablet core: calcium hydrogen phosphate dihydrate, microcrystalline cellulose, crospovidone, povidone, and magnesium stearate. The tablet film-coat contains the following inactive ingredients: hypromellose 2910, macrogol 300, and titanium dioxide E171.
Vandetanib is chemically described as N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl) methoxy]quinazolin-4-amine.
The structural and molecular formulas are:
Vandetanib has a molecular weight of 475.36. Vandetanib exhibits pH-dependent solubility, with increased solubility at lower pH. Vandetanib is practically insoluble in water with a value of 0.008 mg/mL at 25°C (77°F ).
12. CLINICAL PHARMACOLOGY
. Mechanism of Action
Vandetanib is a tyrosine kinase inhibitor. In vitro studies have shown that Vandetanib inhibits the activity of tyrosine kinases including members of the epidermal growth factor receptor (EGFR) family, vascular endothelial cell growth factor (VEGF) receptors, rearranged during transfection (RET), protein tyrosine kinase 6 (BRK), TIE2, members of the EPH receptors kinase family, and members of the Src family of tyrosine kinases. Vandetanib inhibits endothelial cell migration, proliferation, survival and new blood vessel formation in in vitro models of angiogenesis. Vandetanib inhibits EGFR-dependent cell survival in vitro. In addition, Vandetanib inhibits epidermal growth factor (EGF)-stimulated receptor tyrosine kinase phosphorylation in tumor cells and endothelial cells and VEGF-stimulated tyrosine kinase phosphorylation in endothelial cells.
In vivo Vandetanib administration reduced tumor cell-induced angiogenesis, tumor vessel permeability, and inhibited tumor growth and metastasis in mouse models of cancer.
There is no evidence of a relationship between RET mutations and efficacy with Vandetanib.
. Pharmacokinetics
A population pharmacokinetic analysis of Vandetanib was conducted in 231 patients with MTC following oral administration of 300 mg daily doses. The pharmacokinetics of Vandetanib at the 300 mg dose in MTC patients are characterized by a mean clearance of approximately 13.2 L/h, a mean volume of distribution of approximately 7450 L, and a median plasma half-life of 19 days.
Absorption
Following oral administration of Vandetanib, absorption is slow with peak plasma concentrations typically achieved at a median of 6 hours, range 4-10 hours, after dosing. Vandetanib accumulates approximately 8-fold on multiple dosing with steady state achieved from approximately 3 months.
Exposure to Vandetanib is unaffected by food.
Distribution
Vandetanib binds to human serum albumin and α1-acid-glycoprotein with in vitro protein binding being approximately 90%. In ex vivo plasma samples from colorectal cancer patients at steady state exposure after 300 mg once daily, the mean percentage protein binding was 93.7% (range 92.2 to 95.7%).
Metabolism
Following oral dosing of 14C-Vandetanib, unchanged vandentanib and metabolites Vandetanib N-oxide and N-desmethyl Vandetanib were detected in plasma, urine and feces. A glucuronide conjugate was seen as a minor metabolite in excreta only. N-desmethyl-Vandetanib is primarily produced by CYP3A4 and Vandetanib-N-oxide by flavin |
