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Mechanism Of Actionhttp://www.rxlist.com/bystolic-drug.htm
In vitro studies have shown that vandetanib inhibits the tyrosine kinase activity of the EGFR and VEGFR families, RET, BRK, TIE2, and members of the EPH receptor and Src kinase families. These receptor tyrosine kinases are involved in both normal cellular function and pathologic processes such as oncogenesis, metastasis, tumor angiogenesis, and maintenance of the tumor microenvironment. In addition, the N-desmethyl metabolite of the drug, representing 7 to 17.1% of vandetanib exposure, has similar inhibitory activity to the parent compound for VEGF receptors (KDR and Flt-1) and EGFR.
In vitro, vandetanib inhibited 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.
In 231 patients with medullary thyroid cancer 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 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 occurred [see BOX WARNING and WARNINGS AND PRECAUTIONS].
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.
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. Vandetanib accumulates approximately 8-fold on multiple dosing with steady state achieved in approximately 3 months.
Exposure to vandetanib is unaffected by food
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 94%.
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 FMO1 and FMO3. N-desmethylvandetanib and vandetanib-N-oxide circulate at concentrations of approximately 7–17% and 1.4–2.2%, respectively, of those of vandetanib.
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 2.1 μg/mL. This is higher than vandetanib plasma concentrations (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.
Effects Of Age And Gender
In a population pharmacokinetic evaluation in cancer patients, no relationship was apparent between oral clearance of vandetanib and patient age or gender.
Based on a cross-study comparison in a limited number of patients, Japanese (N=3) and Chinese (N=7) patients had average exposures of vandetanib that were higher than Caucasian (N=7) patients receiving the same dose of CAPRELSA.
The pharmacokinetics of vandetanib has not been evaluated in pediatric patients.
Effect Of Renal Impairment
The pharmacokinetics of vandetanib were evaluated after a single CAPRELSA dose of 800 mg in six subjects with mild (creatinine clearance = 50 to < 80 mL/min), eight subjects with moderate (creatinine clearance ≥30 to <50 mL/min), six subjects with severe (creatinine clearance < 30 mL/min) renal impairment and ten subjects with normal (creatinine clearance > 80 mL/min) renal function. Subjects with mild renal impairment had a comparable mean AUC of vandetanib to that with normal renal function. In subjects with moderate or severe renal impairment, the average AUC of vandetanib increased by 39% and 41%, respectively, compared to patients with normal renal function [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS and Use In Specific Populations].
Effect Of Other Drugs On CAPRELSA
Strong CYP3A4 inducers: In a cross-over study in 12 healthy volunteers, a single oral 300 mg dose of CAPRELSA was administered alone on day 1 and on day 10 in combination with daily doses of 600 mg of rifampicin (a strong CYP3A4 inducer) given on days 1–31. The coadministration of rifampicin with CAPRELSA decreased the geometric mean AUC0–504h of vandetanib by 40% (90% confidence interval (CI): 56%, 63%) compared to vandetanib alone. No clinically meaningful change in the mean C of vandetanib was observed. The geometric mean AUC0–504h and Cmax of N-desmethylvandetanib increased by 266% and 414%, respectively, in the presence of rifampicin compared with vandetanib alone [see DRUG INTERACTIONS].
Strong CYP3A4 inhibitors: In a cross-over study in 14 healthy volunteers, a single oral 300 mg dose of CAPRELSA was administered alone and on day 4 in combination with daily doses of 200 mg of itraconazole (a strong CYP3A4 inhibitor) given on days 1–24. No change was observed in the geometric mean AUC0–504h or Cmax of vandetanib when itraconazole was coadministered with CAPRELSA.
Gastric pH elevating agents: In a cross-over study of 14 healthy volunteers, a single oral 300 mg dose of CAPRELSA was administered alone and in combination with five daily doses of 40 mg omeprazole (a proton pump inhibitor). No clinically meaningful change was observed in the geometric mean AUC0–504h and Cmax of vandetanib when omeprazole was coadministered with CAPRELSA.
In a cross-over study of 16 healthy volunteers, a single 300 mg oral dose of CAPRELSA was administered alone and after two oral doses of 150 mg of ranitidine (a H receptor antagonist) administered about 12 hours apart. No change was observed in the geometric mean AUC0–504h and Cmax of vandetanib when ranitidine was coadministered with CAPRELSA.
Effect Of CAPRELSA On Other Drugs
Sensitive CYP3A4 substrates: In a cross-over study of 16 healthy volunteers, a single oral 7.5 mg dose of midazolam (as 2 mg/mL oral syrup), a sensitive CYP3A4 substrate, was administered alone and 8 days after receiving a single 800 mg oral dose of CAPRELSA. No change was observed in the geometric mean Cmax and AUCinf of midazolam when CAPRELSA was coadministered with midazolam.
Substrates of OCT2 transporter: In a cross-over study of 13 healthy volunteers, a single 1000 mg oral dose of metformin, a substrate of OCT2, was administered alone and 3 hours after receiving a single 800 mg oral dose of CAPRELSA. The coadministration of CAPRELSA with metformin increased the geometric mean AUC of metformin by 74% (90% CI: 58%, 92%) and geometric mean C of metformin by 50% (90% CI: 34%, 67%) compared to metformin alone [see DRUG INTERACTIONS].
Substrates of P-glycoprotein transporter: In a cross-over study of 14 healthy volunteers, a single oral 0.25 mg dose of digoxin, a substrate of P-glycoprotein, was administered alone and in combination with a single 300 mg oral dose of CAPRELSA. The coadministration of CAPRELSA increased the geometric mean C digoxin by 29% (90% CI: 10%, 52%) and the geometric mean of AUC of digoxin by 23% (90% CI: 12%, 34%) compared to digoxin alone [see DRUG INTERACTIONS].
Animal Toxicology And/Or Pharmacology
In an animal model of wound-healing, mice dosed with vandetanib had reduced skin-breaking strength compared with controls. This suggests that CAPRELSA slows but does not prevent wound healing. The appropriate interval between discontinuation of CAPRELSA and subsequent elective surgery required to avoid the risks of impaired wound healing has not been determined.
Nodular masses were observed in a 6-month toxicology study in rats during treatment with ≥5 mg/kg/day vandetanib (approximately 0.22 or 0.40 times, respectively, the AUC in patients with cancer at the recommended human dose of 300 mg/day). Masses were palpable during clinical assessments as early as week 13, were observed in multiple organs, and were associated with hemorrhagic or inflammatory findings.
The primary objective was demonstration of improvement in progression-free survival (PFS) with CAPRELSA compared to placebo. Other endpoints included evaluation of overall survival and overall objective response rate (ORR). Centralized, independent blinded review of the imaging data was used in the assessment of PFS and ORR. Upon objective disease progression based on the investigator's assessment, patients were discontinued from blinded study treatment and given the option to receive open-label CAPRELSA. Nineteen percent (44/231) of the patients initially randomized to CAPRELSA opted to receive open-label CAPRELSA after disease progression, and 58% (58/100) of the patients initially randomized to placebo opted to receive open-label CAPRELSA after disease progression.
The result of the PFS analysis, based on the central review RECIST assessment, showed a statistically significant improvement in PFS for patients randomized to CAPRELSA (Hazard Ratio (HR) = 0.35; 95% Confidence Interval (CI) = 0.24–0.53; p<0.0001). Analyses in the subgroups of patients who were symptomatic or had progressed within 6 months prior to their enrollment showed similar PFS results (HR = 0.31 95% CI: 0.19, 0.53 for symptomatic patients; HR = 0.41 95% CI: 0.25, 0.66 for patients who had progressed within 6 months prior to enrollment).
At the time of the primary analysis of PFS, 15% of the patients had died and there was no significant difference in overall survival between the two treatment groups. The overall objective response rate (ORR) for patients randomized to CAPRELSA was 44% compared to 1% for patients randomized to placebo. All objective responses were partial responses.
Figure 1- Progression Free Survival
Table 3 - Summary of Key Efficacy Findings
|PROGRESSION-FREE SURVIVAL||N*||Median PFS (95% CI)||HR†||95% CI||p-value‡|
|CAPRELSA 300 mg||59/231
|Not reached (22.6 months, NE§ )|
|16.4 Months (8.3, 19.7)|
|*N = Number of events/number of randomized patients
†HR= Hazard Ratio, Cox Proportional Hazards Model
§NE = non-estimatable
Last reviewed on RxList: 3/6/2017
This monograph has been modified to include the generic and brand name in many instances.
Additional Caprelsa Information
- Caprelsa Drug Interactions Center: vandetanib oral
- Caprelsa Side Effects Center
- Caprelsa FDA Approved Prescribing Information including Dosage
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