Chemical formula: C₂₂H₂₄BrFN₄O₂ Molecular mass: 475.354 g/mol PubChem compound: 3081361
Vandetanib is a potent inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2 also known as kinase insert domain containing receptor [KDR]), epidermal growth factor receptor (EGFR) and RET tyrosine kinases. Vandetanib is also a sub-micromolar inhibitor of vascular endothelial receptor-3 tyrosine kinase.
Vandetanib inhibits VEGF-stimulated endothelial cell migration, proliferation, survival and new blood vessel formation in in vitro models of angiogenesis. In addition, vandetanib inhibits epidermal growth factor (EGF)-stimulated EGF receptor tyrosine kinase in tumour cells and endothelial cells. Vandetanib inhibits EGFR-dependent cell proliferation and cell survival in vitro. Vandetanib also inhibits both wild type and the majority of mutated, activated forms of RET, and significantly inhibits the proliferation of MTC cell lines in vitro.
In vivo vandetanib administration reduced tumour cell-induced angiogenesis, tumour vessel permeability, tumour microvessel density, and inhibited tumour growth of a range of human xenograft tumour models in athymic mice. Vandetanib also inhibited the growth of MTC xenograft tumours in vivo.
The precise mechanism of action of vandetanib in locally advanced or metastatic MTC is unknown.
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 2 months.
Vandetanib binds to human serum albumin and alpha-1-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%). The pharmacokinetics of vandetanib at the 300 mg dose in MTC patients are characterised by a volume of distribution of approximately 7450 l.
Following oral dosing of 14C-vandetanib, unchanged vandetanib 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-containing monooxygenase enzymes (FM01 and FMO3). N-desmethyl-vandetanib and vandetanib-N-oxide circulate at concentrations of approximately 11% and 1.4% of those of vandetanib.
The pharmacokinetics of vandetanib at the 300 mg dose in MTC patients are characterised by a clearance of approximately 13.2 l/h. and plasma half-life of approximately 19 days. Within a 21 day collection period after a single dose of 14C-vandetanib, approximately 69% was recovered with 44% in faeces and 25% in urine. Excretion of the dose was slow and further excretion beyond 21 days would be expected based on the plasma half-life.
A single dose pharmacokinetic study in volunteers indicated that exposure to vandetanib is enhanced (up to 1.5, 1.6 and 2-fold) in mild, moderate and severe renal impaired subjects respectively compared to subjects with normal renal function.
A single dose pharmacokinetic study in volunteers indicated that hepatic impairment did not affect exposure to vandetanib. There is limited data in patients with hepatic impairment (serum bilirubin greater than 1.5 times upper limit of normal.
Exposure to vandetanib is not affected by food.
The pharmacokinetic parameters of vandetanib in paediatrics MTC patients aged 9-17 years were similar to those in adults. Vandetanib exposure in children between 5-8 years old with glioma-related indications was comparable to MTC patients aged 9-18 years. Dosing at 100mg/m 2/day of the indicated posology (function of BSA) in paediatrics delivers similar exposure to that achieved in adults at 300 mg daily.
Vandetanib has shown no mutagenic or clastogenic potential.
In repeat-dose toxicity studies of up to 9 months duration, effects included emesis, body weight loss and diarrhoea in dogs and physeal dysplasia in young dogs and rats with open growth plates. In rats, effects on teeth, kidney and skin were noted. These findings occurred at clinically-relevant plasma concentrations, were largely reversible within 4 weeks of cessation of dosing and were attributable to inhibition of vascular endothelial growth factor receptor (VEGFR) or EGFR.
Effects noted in other studies included inhibition of human ether-à-go-go related gene (hERG) current and prolongation of QTc interval in dogs. Elevation of systolic and diastolic blood pressure was observed in rats and dogs. In mice, vandetanib was shown to delay but not prevent wound healing. Vandetanib also showed evidence of phototoxic potential in an in vitro cytotoxicity assay. In an animal model of wound-healing, mice dosed with vandetanib had reduced skin-breaking strength compared with controls. This suggests that vandetanib slows but does not prevent wound healing. The appropriate interval between discontinuation of vandetanib and subsequent elective surgery required to avoid the risks of impaired wound healing has not been determined. In clinical studies, a small number of patients had surgery while receiving vandetanib and there were no reported wound healing complications.
Vandetanib had no effect on fertility in male rats. In a female fertility study, there was a trend towards increased oestrus cycle irregularity, a slight reduction in pregnancy incidence and increase in implantation loss. In a repeat-dose toxicity study in rats, there was a decrease in the number of corpora lutea in the ovaries of rats given vandetanib for 1 month.
In rats, embryofoetal toxicity was evident as foetal loss, delayed foetal development, heart vessel abnormalities and precocious ossification of some skull bones. In a rat pre- and post-natal development study, at doses producing maternal toxicity during gestation and/or lactation, vandetanib increased pre-birth loss and reduced post-natal pup growth. Vandetanib was excreted into milk in rat and found in plasma of pups following dosing to lactating rats.
Vandetanib has shown no carcinogenic potential effect in a 6 month carcinogenicity study in rasH2 transgenic mice. A 2-year carcinogenicity study in rats was impaired by low survival in the high dose female group and limited exposure of the animals to vandetanib; however, no carcinogenic effects were observed in the remaining animals.
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