of a relationship between RET mutations and efficacy with vandetanib.
12.3. Pharmacokinetics
A population pharmacokinetic analysis of CAPRELSA was conducted in 231 patients with MTC following oral administration of 300 mg daily doses. The pharmacokinetics of CAPRELSA 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 CAPRELSA, absorption is slow with peak plasma concentrations typically achieved at a median of 6 hours, range 4-10 hours, after dosing. CAPRELSA 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–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 CAPRELSA have not been eva luated in pediatric patients.
12.4 QT Prolongation
In 231 medullary thyroid cancer patients randomized to receive CAPRELSA 300 mg once daily in the phase 3 clinical trial, CAPRELSA 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 g |
