–containing monooxygenase enzymes FMO1 and FMO3. N-desmethyl-Vandetanib and Vandetanib-N-oxide circulate at concentrations of approximately 7-17.1% and 1.4-2.2%, respectively, of those of Vandetanib.
Excretion
Within a 21-day collection period after a single dose of 14C-Vandetanib, approximately 69% was recovered with 44% in feces 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.
Vandetanib was not a substrate of hOCT2 expressed in HEK293 cells. Vandetanib inhibits the uptake of the selective OCT2 marker substrate 14C-creatinine by HEK-OCT2 cells, with a mean IC50 of approximately 2.1 μg/mL. This is higher than Vandetanib plasma concentrations (approximately 0.81 μg/mL) observed after multiple dosing at 300 mg. Inhibition of renal excretion of creatinine by Vandetanib provides an explanation for increases in plasma creatinine seen in human subjects receiving Vandetanib.
Special Populations
Effects of Age and Gender
In a population pharmacokinetic eva luation in cancer patients, no relationship was apparent between oral clearance and patient age or gender.
Ethnicity
Based on a cross-study comparison in a limited number of patients, Japanese (N=3) and Chinese (N=7) patients had on average exposures that were higher than Caucasian (N=7) patients receiving the same dose.
Pediatric
The pharmacokinetics of Vandetanib have not been eva luated in pediatric patients.
QT Prolongation
In 231 medullary thyroid cancer patients randomized to receive Vandetanib 300 mg once daily in the phase 3 clinical trial, Vandetanib was associated with sustained plasma concentration-dependent QT prolongation. Based on the exposure-response relationship, the mean (90% CI) QTcF change from baseline (ΔQTcF) was 35 (33-36) ms for the 300-mg dose. The ΔQTcF remained above 30 ms for the duration of the trial (up to 2 years). In addition, 36% of patients experienced greater than 60 ms increase in ΔQTcF and 4.3% of patients had QTcF greater than 500 ms. Cases of Torsades de pointes and sudden death have been reported [see Warnings and Precautions (5.1, 5.11)].
13. NONCLINICAL TOXICOLOGY
. Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies have not been conducted with Vandetanib.
Vandetanib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay and was not clastogenic in both the in vitro cytogenetic assay using human lymphocytes or in the in vivo rat micronucleus assay.
Based on nonclinical findings, male and female fertility may be impaired by treatment with Vandetanib. In a fertility study in male rats, Vandetanib had no effect on copulation or fertility rate when undosed females were mated with males administered 1, 5, or 20 mg/kg/day of Vandetanib (approximately 0.03, 0.22, or 0.40 times, respectively, the AUC in patients with cancer at the recommended human dose of 300 mg/day). There was a slight decrease in the number of live embryos at 20 mg/kg/day and an increase in preimplantation loss at >5 mg/kg/day. In a female fertility study, there was a trend towards increased estrus cycle irregularity, a slight reduction in pregnancy incidence and an 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 administered 75 mg/kg/day Vandetanib (approximately 1.8 times the AUC in patients with cance |
