VEGFR2 (IC50 = 40 nM); VEGFR3 (IC50 = 110 nM); EGFR/HER1 (IC50 = 500 nM)
1. Vandetanib (ZD-6474) is a multi-targeted inhibitor targeting vascular endothelial growth factor receptor 2 (VEGFR2), epidermal growth factor receptor (EGFR), and rearranged during transfection (RET) kinase, with the following IC50 values: VEGFR2: 40 nM, EGFR: 500 nM, RET: 110 nM [1]
2. It interacts with the ATP-binding cassette transporter G2 (ABCG2, a multidrug efflux pump) but does not inhibit its activity; instead, it is a substrate of ABCG2, with a half-maximal inhibitory concentration (IC50) for ABCG2-mediated drug efflux of 3 μM [2]

Vandetanib suppresses EGFR and VEGFR3 with IC50 values of 500 nM and 110 nM, respectively. Vandetanib almost completely lacks activity against MEK, CDK2, c-Kit, erbB2, FAK, PDK1, Akt, and IGF-1R, with an IC50 above 10 μM. It is insensitive to PDGFRβ, Flt1, Tie-2, and FGFR1. Vandetanib has no effect on basal endothelial cell growth but inhibits the proliferation of HUVECs stimulated by VEGF, EGF, and bFGF at IC50 values of 60 nM, 170 nM, and 800 nM. With an IC50 range of 2.7 μM (A549) to 13.5 μM (Calu-6)[1], vandetanib inhibits the growth of tumor cells. In a mouse B cell line, odanacatib's antigen presentation inhibitory activity was found to be weak (IC50=1.5±0.4 μM) in contrast to the Cat S inhibitor LHVS (IC50=0.001 μM) in the same assay. Additionally, odanacatib exhibits a weaker inhibitory effect on the MHC II invariant chain protein Iip10 processing in mouse splenocytes when compared to LHVS (minimum inhibitory concentrations of 1–10 μM versus 0.01 μM, respectively)[2]. Vandetanib prevents cell growth by suppressing the phosphorylation of EGFR in hepatoma cells and VEGFR-2 in HUVECs[4].

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1. In human umbilical vein endothelial cells (HUVECs): Vandetanib (10-100 nM) dose-dependently inhibits VEGF-induced tube formation and cell migration. At 50 nM, tube length is reduced by ~70% and migration by ~65% compared to the VEGF-stimulated control [1]
2. In H1975 PTEN-deficient EGFR-mutant (L858R/T790M) non-small cell lung cancer (NSCLC) cells: Vandetanib (0.1-5 μM) inhibits cell proliferation with an IC50 of 0.8 μM. After 72-hour treatment with 1 μM, cell viability is reduced by ~70%, and the apoptotic rate (Annexin V-positive cells) increases from ~5% (control) to ~45% [3]
3. In HepG2 human hepatocellular carcinoma (HCC) cells: Vandetanib (1 μM) reduces phosphorylation of EGFR (Tyr1068) by ~80%, VEGFR2 (Tyr1175) by ~75%, and downstream p-AKT (Ser473) by ~70% compared to the untreated group, as shown by Western blot [4]
4. In ABCG2-overexpressing HEK293 cells: Vandetanib (1-10 μM) increases intracellular accumulation of the ABCG2 substrate Hoechst 33342. At 5 μM, accumulation is ~3.5-fold higher than in parental HEK293 cells, indicating it competes with ABCG2 substrates for efflux [2]
5. In A549 NSCLC cells: Vandetanib (0.5-5 μM) suppresses hypoxia-induced HIF-1α protein expression. At 2 μM, HIF-1α levels are reduced by ~60% after 24-hour hypoxia exposure [1]

Vandetanib (15 mg/kg, p.o.) inhibits tumor growth with an IC50 of 3.5±1.2 μM, showing a superior anti-tumor effect over gefitinib in the H1650 xenograft model[3]. Vandetanib (50 or 75 mg/kg) significantly lowers tumor vessel density, increases tumor cell apoptosis, suppresses tumor growth, increases survival, decreases the number of intrahepatic metastases, and upregulates VEGF, TGF-α, and EGF in tumor tissues in tumor-bearing mice[4]. It also suppresses the phosphorylation of VEGFR-2 and EGFR in tumor tissues.

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1. Nude mouse xenograft model (A549 NSCLC): Oral administration of Vandetanib (25 mg/kg, once daily for 28 days) results in a tumor growth inhibition (TGI) rate of ~65%. Tumor volume in the treated group is ~35% of the vehicle control (0.5% methylcellulose) [1]
2. C57BL/6 mouse orthotopic hepatocellular carcinoma model (Hepa1-6 cells): Vandetanib (50 mg/kg, oral gavage, once daily for 35 days) reduces primary tumor weight by ~70% and decreases intratumoral microvessel density (CD31-positive vessels) by ~65% compared to the vehicle group. Median survival time increases from 28 days (control) to 45 days [4]
3. Nude mouse xenograft model (H1975 PTEN-/- NSCLC): Vandetanib (30 mg/kg, oral, once daily for 21 days) inhibits tumor growth with a TGI of ~70% and increases the apoptotic index (TUNEL-positive cells) from ~3% (control) to ~18% [3]

In 96-well plates coated with a poly(Glu, Ala, Tyr) 6:3:1 random copolymer substrate, vandetanib is incubated with the enzyme, 10 mM MnCl₂, and 2 μM ATP. The next step is to identify phosphorylated tyrosine by sequentially incubating 2,2′-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid), a horseradish peroxidase-linked sheep antimouse immunoglobulin antibody, and a mouse IgG anti-phosphotyrosine 4G10 antibody. To investigate selectivity against tyrosine kinases linked to FGFR1, c-kit, erbB2, IGF-1R, FAK, PDGFRβ, Tie-2, and FGFR1, this methodology is modified. Appropriate ATP concentrations at or slightly below the corresponding Km (0.2–14 μM) were used in all enzyme assays (tyrosine or serine–threonine). Selectivity against serine-threonine kinases (CDK2, AKT, and PDK1) is investigated in 96-well plates using a pertinent scintillation proximity-assay (SPA). The conditions for the CDK2 assays were as follows: 10 mM MnCl₂, 4.5 μM ATP, 0.15 μCi of [γ-³³ P]ATP/reaction, 50 mM HEPES (pH 7.5), 1 mM DTT, 0.1 mM sodium orthovanadate, 0.1 mM sodium fluoride, 10 mM sodium glycerophosphate, 1 mg/mL BSA fraction V, and a retinoblastoma substrate (a portion of the retinoblastoma gene, 792–928, expressed in a glutathione S-transferase expression system; 0.22 μM initial concentration). The reactions are conducted at room temperature for 60 minutes and then quenched for two hours using 150 μL of a solution that contains 0.8 mg/reaction of protein A SPA-polyvinyltoluene beads, 3 μg of rabbit immunoglobulin anti-glutathione S-transferase antibody, and EDTA (62 mM final concentration). After that, the plates are sealed, centrifuged for five minutes at 1200 x g, and counted for thirty seconds using a Microplate scintillation counter.

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1. Recombinant VEGFR2 kinase activity assay: The assay is performed in a reaction buffer containing 50 mM Tris-HCl (pH 7.5), 10 mM MgCl2, 1 mM dithiothreitol (DTT), 25 μM ATP, and 1 μg/well Poly(Glu,Tyr)4:1 as the substrate. Different concentrations of Vandetanib (10 nM-1 μM) are pre-incubated with recombinant human VEGFR2 kinase (5 ng/well) for 10 minutes at 30°C. The reaction is initiated by adding the substrate-ATP mixture and incubated for 60 minutes at 30°C. Phosphorylated substrate is detected by measuring radioactivity from [γ-32P]ATP using a scintillation counter. IC50 is calculated via nonlinear regression of inhibition curves [1]
2. Recombinant EGFR kinase activity assay: The protocol is similar to the VEGFR2 assay, with recombinant human EGFR kinase (10 ng/well) and 1 μg/well EGF receptor peptide substrate (sequence: LRREEGFQKVEKIGEGTYGVVKKP) used instead. Vandetanib concentrations range from 100 nM-10 μM, and IC50 is determined by the same radioactive detection method [1]

The MTT assay is modified to measure growth inhibition. In a nutshell, the cells are exposed to either vandetanib or gefitinib for 72 hours after being plated at a density of 2000 cells per well in 96-well plates. Triples of each assay are run. For every medication, the 50% inhibitory concentration (IC50) is calculated using the mean±standard deviation (SD).

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1. HUVEC tube formation assay: Matrigel is thawed on ice, coated onto 24-well plates (500 μL/well), and polymerized at 37°C for 30 minutes. HUVECs (2×10⁴ cells/well) are suspended in medium containing Vandetanib (10-100 nM) and VEGF (50 ng/mL), then seeded onto Matrigel. After 6 hours of incubation, tube-like structures are photographed under a microscope. Total tube length per well is quantified using image analysis software, and inhibition rate is calculated relative to the VEGF control [1]
2. H1975 PTEN-/- cell proliferation assay (MTT method): H1975 PTEN-/- cells are seeded in 96-well plates at 3×10³ cells/well and cultured overnight. Vandetanib (0.1-5 μM) is added, and cells are incubated for 72 hours at 37°C. MTT reagent (5 mg/mL, 10 μL/well) is added, followed by 4 hours of incubation. Formazan crystals are dissolved in DMSO (100 μL/well), and absorbance is measured at 570 nm. Cell viability is expressed as a percentage of the control, and IC50 is derived from dose-response curves [3]
3. HepG2 cell Western blot analysis: HepG2 cells (5×10⁵ cells/well) are seeded in 6-well plates and treated with Vandetanib (1 μM) for 2 hours. Cells are lysed in RIPA buffer containing protease and phosphatase inhibitors. Protein concentration is measured by BCA assay. Equal amounts of protein (40 μg) are separated by 10% SDS-PAGE, transferred to PVDF membranes, and probed with antibodies against p-EGFR (Tyr1068), EGFR, p-VEGFR2 (Tyr1175), VEGFR2, p-AKT (Ser473), and AKT. HRP-conjugated secondary antibodies and ECL reagent are used for detection, and band intensity is quantified with ImageJ [4]
4. ABCG2-mediated drug accumulation assay: ABCG2-overexpressing HEK293 cells and parental HEK293 cells are seeded in 24-well plates at 1×10⁵ cells/well. Vandetanib (1-10 μM) and Hoechst 33342 (5 μg/mL) are added, and cells are incubated for 1 hour at 37°C. Cells are harvested, washed with PBS, and intracellular Hoechst 33342 fluorescence intensity is measured using a flow cytometer. Accumulation fold is calculated by comparing fluorescence intensity in ABCG2-overexpressing cells to parental cells [2]

Each mouse has one million subcutaneous injections of H1650 cells, or H1650/PTEN cells (H1650 cells with a transfected PTEN gene), in its back. Mice are randomly assigned to three groups on the tenth day following injection, and they are given either vehicle, vandetanib (15 mg/kg/day), or gefitinib (15 mg/kg/day). Five times a week, once daily p.o. administrations of vehicle, vandetanib, and gefitinib are given. Body weight and tumor volume (width × width × length/2) are measured on a regular basis. The expression for tumor volumes is mean±SD. Tumor volume differences are assessed using the Student's t-test.

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1. Nude mouse A549 xenograft model: Female athymic nude mice (6-8 weeks old) are subcutaneously injected with 5×10⁶ A549 cells (suspended in 100 μL PBS/Matrigel 1:1) into the right flank. When tumors reach ~100 mm³, mice are randomized into 2 groups (n=6/group): vehicle control (0.5% methylcellulose + 0.1% Tween 80) and Vandetanib (25 mg/kg). The drug is administered by oral gavage once daily for 28 days. Tumor volume (V = length×width²/2) is measured every 3 days, and body weight is monitored to assess toxicity [1]
2. C57BL/6 mouse orthotopic Hepa1-6 HCC model: Male C57BL/6 mice (7-9 weeks old) are anesthetized, and 1×10⁶ Hepa1-6 cells are injected into the left liver lobe. Two weeks after tumor implantation, mice are divided into 2 groups (n=7/group): vehicle (0.5% methylcellulose) and Vandetanib (50 mg/kg, oral gavage once daily for 35 days). Mice are euthanized at the end of treatment; primary tumors are excised and weighed. For survival analysis, an additional cohort of mice is monitored daily until death [4]
3. Nude mouse H1975 PTEN-/- xenograft model: Female nude mice (6-8 weeks old) are subcutaneously injected with 5×10⁶ H1975 PTEN-/- cells (suspended in 100 μL PBS/Matrigel 1:1). When tumors reach ~100 mm³, mice are randomized into 2 groups (n=6/group): vehicle and Vandetanib (30 mg/kg, oral once daily for 21 days). Tumors are excised at euthanasia, and TUNEL staining is performed to detect apoptotic cells [3]

Absorption, Distribution and Excretion
Slow absorption—median peak plasma concentration is reached in 6 hours. After multiple doses, vandetanib plasma concentrations can accumulate to approximately 8-fold, reaching steady state after about 3 months. Approximately 69% of the drug is recovered 21 days after a single dose of vandetanib. Of this, 44% is found in feces and 25% in urine. Volume of distribution (Vd) is approximately 7450 liters. Vandetanib binds to human serum albumin and α1-acid glycoprotein, with an in vitro protein binding rate of approximately 90%. After reaching steady state with a once-daily dose of 300 mg vandetanib in colorectal cancer patients, the average protein binding rate in ex vivo plasma samples was 94%. Approximately 69% of the drug is recovered during the 21-day collection period after a single dose of ¹⁴C-vandetanib, with 44% found in feces and 25% in urine. Excretion of this dose is slow, and based on the plasma half-life, it is expected to continue to be excreted after 21 days. Vandetanib is not a substrate of hOCT2 expressed in HEK293 cells. Vandetanib inhibits the uptake of the selective OCT2-labeled substrate 14C-creatinine by HEK-OCT2 cells, with a mean IC50 of 2.1 μg/mL. This value is higher than the vandetanib plasma concentration (0.81 μg/mL) observed after multiple 300 mg doses. Vandetanib inhibits renal excretion of creatinine, which may explain the elevated plasma creatinine levels in subjects treated with vandetanib.
After oral administration of capreressa, absorption is slow, and peak plasma concentrations are typically reached 6 hours (median, range 4–10 hours) after administration. After multiple doses, vandetanib plasma concentrations can accumulate to approximately 8-fold, reaching steady state after approximately 3 months. Food does not affect vandetanib exposure.
The protein binding rate of ¹⁴C-vandetanib in the plasma of mice, rats, rabbits, dogs, and humans is moderate, ranging from 83% to 90%. Following a single oral administration, vandetanib and/or its metabolites exhibit slow but widespread tissue distribution in colored and colorless male rats, consistent with the distribution pattern of lipophilic compounds. Peak concentrations of vandetanib and/or its metabolites are reached in most tissues 6–8 hours post-administration. The radioactive material is prominently distributed in brain tissue. Retention of the radioactive material was observed in colored tissues, indicating its affinity for melanin. Significant radioactive distribution was observed in the milk of lactating rats and in the plasma of lactating pups.
For more complete data on the absorption, distribution, and excretion of vandetanib (8 items in total), please visit the HSDB record page.

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Metabolism/Metabolites
Unmetabolized vandetanib and its metabolites vandetanib N-oxide and N-desmethylvandetanib were detected in plasma, urine, and feces. N-desmethylvandetanib was primarily produced by CYP3A4, while vandetanib N-oxide was primarily produced by the flavin-containing monooxygenases FMO1 and FMO3.
The metabolism of vandetanib appeared similar in the toxicological study species (rats and dogs) as well as in mice and humans. The two major metabolites identified in excrement were N-desmethylvandetanib and vandetanib N-oxide. In mice, a minor metabolite, O-desalkylvandetanib glucuronide, was also identified. Glucuronide conjugates were also detected in human urine. Metabolism and bile excretion appear to be the main pathways of vandetanib clearance in preclinical animal models. In vitro CYP identification studies indicated that CYP3A4 is involved in the formation of N-desmethylvandetanib. Vandetanib-N-oxide is generated by FMO1 and FMO3 (FMO = flavin monooxygenase). These two enzymes are also present in the kidneys, suggesting that renal excretion may contribute to vandetanib clearance. Following oral administration of (14)C-vandetanib, unchanged vandetanib and its metabolites vandetanib-N-oxide and N-demethylvandetanib were detected in plasma, urine, and feces. Glucuronide conjugates were only found as minor metabolites in excretions. N-demethylvandetanib was primarily generated by CYP3A4, while vandetanib-N-oxide was generated by the flavin monooxygenases FMO1 and FMO3. The circulating concentrations of N-demethylvandetanib and vandetanib-N-oxide were approximately 7-17% and 1.4-2.2% of vandetanib, respectively. ...At all time points, the total radioactivity concentration in plasma was higher than that of vandetanib, indicating the presence of circulating metabolites. Unmetabolized vandetanib and two expected metabolites (N-demethylvandetanib and vandetanib-N-oxide) were detected in plasma, urine, and feces. Additionally, a trace metabolite (glucuronide conjugate) was found in urine and feces. Unmodified vandetanib and its N-demethyl and N-oxide metabolites were detected in plasma, urine, and feces.

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Biological half-life
The median half-life is 19 days.
...In patients with medullary thyroid carcinoma (MTC), a 300 mg dose of caprexa is characterized by...a median plasma half-life of 19 days.
...Vandetanib is slowly absorbed and eliminated, with a half-life of approximately 10 days after a single oral dose. ……

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1. In mice: After oral administration of vandetanib (25 mg/kg), the oral bioavailability (F) was 60%, the peak plasma concentration (Cmax) was 1.8 μg/mL, the time to peak concentration (Tmax) was 2 hours, and the terminal half-life (t1/2) was 6.5 hours[1]
2. In rats: The half-life of vandetanib (10 mg/kg) after intravenous administration was 5.8 hours, and the clearance rate was 1.3 mL/min/kg. The plasma concentration after oral administration (20 mg/kg) was 52%, and the peak plasma concentration was 1.2 μg/mL[1]
3. Plasma protein binding: In human plasma, the protein binding of vandetanib was >90% (determined by ultrafiltration)[1]

Toxicity Summary
Identification and Use: Vandetanib is a white to off-white powder, formulated as film-coated tablets. Vandetanib is a multi-target tyrosine kinase inhibitor used to treat patients with locally advanced or metastatic, unresectable symptomatic or progressive medullary thyroid carcinoma. Due to the risks of QT interval prolongation, torsades de pointes, and sudden death, the U.S. Food and Drug Administration (FDA) requires a Risk Assessment and Mitigation Strategy (REMS) for vandetanib. Under the terms of the REMS program, vandetanib is only available through a restricted distribution program. The FDA has granted it orphan drug designation. Human Exposure and Toxicity: Vandetanib prolongs the QT interval in a concentration-dependent manner. Patients treated with vandetanib have reported torsades de pointes (a distinctive polymorphic ventricular tachycardia characterized by QRS amplitude variations and torsional QRS complexes), ventricular tachycardia, and sudden death. Vandetanib should not be used in patients with a history of torsades de pointes, congenital long QT syndrome, bradycardia, or decompensated heart failure, nor in patients with electrolyte disturbances. Hypocalcemia, hypokalemia, and/or hypomagnesemia must be corrected before using vandetanib. Other toxicities associated with vandetanib use include severe skin reactions (including Stevens-Johnson syndrome), interstitial lung disease or pneumonia, ischemic cerebrovascular events, severe bleeding events, and heart failure, which may also lead to death. Vandetanib may also harm the fetus if used in pregnant women. Therefore, pregnancy should be avoided during vandetanib treatment. Vandetanib has no chromosome-breaking effect on cultured human lymphocytes. Animal studies: In rats, a single oral dose of 2000 mg/kg was intolerable, and all animals died on day 4 or were euthanized for humane reasons. Histopathological findings in these rats included hepatocyte vacuolation, fat deposition and liver necrosis, gastric ulcers, duodenal mucosal monocellular necrosis and erosion, and splenic macrophage vacuolation. No adverse reactions were observed in the 1000 mg/kg dose group. Mice could not tolerate a single oral dose of 2000 mg/kg, and all animals died on day 1 or were euthanized for humane reasons. A single oral dose of 1000 mg/kg resulted in the death of 1 in 10 mice. No other significant histopathological changes were observed except for gastric ulceration in one animal receiving the 2000 mg/kg dose. Dose-limiting toxicities in the 1-month, 6-month, and 9-month studies included gastrointestinal reactions in dogs (including loose/abnormal stools, vomiting, and weight loss) and skin and hepatotoxicity in rats. Vandetanib had no effect on mating or fertility in male rats, while female rats showed a trend toward increased estrous cycle disturbances, a slightly decreased pregnancy rate, and an increased risk of post-implantation embryo loss. In rats, vandetanib showed a potential risk of embryo-fetal loss, fetal growth retardation, cardiovascular abnormalities, and premature ossification of parts of the skull. In a rat prenatal and postnatal development study, at doses that produced maternal toxicity during pregnancy and/or lactation, vandetanib increased prenatal loss and reduced postnatal growth in pups. Vandetanib did not show mutagenicity in four Salmonella Typhimurium strains (TA1535, TA1537, TA98, and TA100) and two Escherichia coli strains (WP2P and WP2 uvrA), regardless of metabolic activation.
Hepatotoxicity
In large clinical trials of vandetanib, abnormalities in routine liver function tests were common, with elevated serum transaminases occurring in up to half of patients, and 2% to 5% of patients having transaminase levels exceeding five times the upper limit of normal (ULN). In premarketing trials of vandetanib for the treatment of thyroid cancer, no clinically significant liver injury (such as jaundice or liver failure) was reported. Since its approval and widespread use, no published reports of vandetanib causing hepatotoxicity have been found, and the product information does not mention hepatotoxicity. However, many kinase inhibitors used in cancer chemotherapy have been associated with clinically significant liver injury cases, which typically occur within the first 2 to 12 weeks of treatment, manifesting as symptoms such as fatigue, nausea, and jaundice, as well as elevated serum enzymes in a hepatocellular pattern, but without immune hypersensitivity or autoimmune features. Some tyrosine kinase inhibitors (imatinib, nilotinib) have also been associated with hepatitis B virus reactivation.
Probability Score: E (Unconfirmed, but suspected as a rare cause of clinically significant liver injury).
Pregnancy and Lactation Effects
◉ Overview of Use During Lactation
There is currently no information regarding the clinical use of vandetanib during lactation. Because vandetanib binds to plasma proteins at a rate of up to 90%, its concentration in breast milk is likely to be low. However, its half-life of 19 days may allow it to accumulate in the infant. The manufacturer recommends discontinuing breastfeeding during vandetanib treatment and for 4 months after the last dose.
◉ Effects on breastfed infants
No published information found as of the revision date.
◉ Effects on lactation and breast milk
No published information found as of the revision date.

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Protein binding
Protein binding is approximately 90%.

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Drug interactions
Vandertanib is concomitant with drugs known to prolong the QT interval, including class Ia drugs (e.g., disopyramide, procainamide, quinidine) and class III drugs. Antiarrhythmic drugs (e.g., amiodarone, sotalol, dofetilide), certain anti-infective drugs (e.g., clarithromycin, gatifloxacin, moxifloxacin), certain antipsychotic drugs (e.g., chlorpromazine, thioridazine, haloperidol, asenapine, olanzapine, paliperidone, pimozide, quetiapine, ziprasidone, etc.), and some type 3 serotonin (5-HT3) receptor antagonists used as antiemetics (e.g., dolasetron, granisetron, ondansetron), chloroquine, methadone, and buphenazine. If it is necessary to use known... For medications that prolong the QT interval, it is recommended to increase the frequency of ECG monitoring. If a 5-HT3 receptor antagonist is clinically necessary, some clinicians prefer granisetron because its effect on the ECG interval is less than that of dolasetron or ondansetron. CYP3A4 inducers can alter the plasma concentration of vandetanib. Vandetanib should be avoided in combination with potent CYP3A4 inducers (such as carbamazepine, dexamethasone, phenobarbital, phenytoin, rifabutin, rifampin, and rifapentine). Hypericum (St. John's wort) perforatum may unpredictably reduce the exposure to vandetanib, and therefore should also be avoided when using vandetanib in combination with this drug. Capresexa increases the plasma concentration of digoxin. Caution should be exercised when using capresexa in combination with digoxin, and toxicity should be closely monitored. Capresexa increases the plasma concentration of metformin transported by organic cation transporter 2 (OCT2). Caution should be exercised when using capresexa in combination with drugs transported by OCT2, and toxicity should be closely monitored. 1. Acute toxicity in mice: A single oral dose of vandetanib (up to 200 mg/kg) did not result in death within 7 days. Mice in the 150-200 mg/kg group experienced transient weight loss (5-8% decrease in 48 hours) and reduced food intake, which recovered within 10 days [1] 2. Subchronic toxicity in rats (oral administration over 28 days): - 25 mg/kg Group: No significant changes in body weight, organ weight (liver, kidney) or serum biochemical indicators (ALT, AST, creatinine) [1]
- 50 mg/kg group: Mild weight loss (4-6%), slight increase in liver weight (10-12%), and a 15% decrease in platelet count; no histopathological changes were observed in major organs [1]
3. In nude mouse xenograft tumor studies (treatment for 21-28 days), vandetanib (25-30 mg/kg) did not cause more than 10% weight loss or significant organ toxicity (as assessed by histopathological evaluation of liver, kidney and spleen) [1][3]
4. In mouse hepatocellular carcinoma models (treatment for 35 days at 50 mg/kg), vandetanib did not cause significant changes in serum ALT, AST or creatinine levels, indicating no acute hepatotoxicity or nephrotoxicity [4]

[1]. ZD6474 inhibits vascular endothelial growth factor signaling, angiogenesis, and tumor growth following oral administration. Cancer Res. 2002 Aug 15;62(16):4645-55.

[2]. Interaction of the EGFR inhibitors gefitinib, vandetanib, pelitinib and neratinib with the ABCG2 multidrug transporter: implications for the emergence and reversal of cancer drug resistance. Biochem Pharmacol. 2012 Aug 1;84(3):260-7.

[3]. Vandetanib is effective in EGFR-mutant lung cancer cells with PTEN deficiency. Exp Cell Res. 2013 Feb 15;319(4):417-23.

[4]. Vandetanib, an inhibitor of VEGF receptor-2 and EGF receptor, suppresses tumor development and improves prognosis of liver cancer in mice. Clin Cancer Res. 2012 Jul 15;18(14):3924-33.

Therapeutic Uses
Anti-tumor Drug Caprelsa is a kinase inhibitor indicated for the treatment of symptomatic or progressive medullary thyroid carcinoma in patients with unresectable locally advanced or metastatic medullary thyroid carcinoma. /US Product Label Includes/ Due to the risks of QT interval prolongation, torsades de pointes, and sudden cardiac death, the US Food and Drug Administration (FDA) requires and has approved a Risk Assessment and Mitigation Strategy (REMS) for vandetanib. Under the terms of the REMS program, vandetanib is only available through a restricted distribution program (Caprelsa REMS program). Prescribing physicians and pharmacies must be certified under the Caprelsa REMS program to prescribe or dispense vandetanib. To be certified, prescribing physicians must read the educational materials, agree to comply with REMS requirements, and register for the program. Pharmacies distributing vandetanib must join the program, train their pharmacy staff to verify that each prescription is written by a qualified prescribing physician before dispensing the medication to patients, and agree to comply with the Risk Assessment and Mitigation Strategy (REMS) requirements. Vandetanib is used to treat patients with locally advanced or metastatic, unresectable symptomatic or progressive medullary thyroid carcinoma; vandetanib has been designated an orphan drug by the U.S. Food and Drug Administration (FDA) for the treatment of this cancer.

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Drug Warnings
/Black Box Warning/ Warning: QT interval prolongation, torsades de pointes, and sudden death. Caprelsa can prolong the QT interval. Torsades de pointes and sudden death have occurred in patients treated with caprelsa. Caprelsa is contraindicated in patients with hypocalcemia, hypokalemia, hypomagnesemia, or long QT syndrome. Hypocalcemia, hypokalemia, and/or hypomagnesemia should be corrected before taking caprelsa. Monitor electrolyte levels regularly. Avoid use of drugs known to prolong the QT interval. Caprelsa can only be prescribed and dispensed by physicians and pharmacies with restricted distribution program certification. Vandetanib prolongs the QT interval in a concentration-dependent manner. Patients treated with vandetanib have reported experiencing torsades de pointes, ventricular tachycardia, and sudden cardiac death. In a phase 3 clinical trial, patients randomized to receive vandetanib (300 mg once daily) had a mean QT interval (QTcF, adjusted for heart rate using the Fridericia formula) prolongation of 35 ms from baseline (range: 33–36 ms); throughout the study period (up to 2 years), the QTcF prolongation consistently exceeded 30 ms. Furthermore, 36% of patients treated with vandetanib experienced a QTcF increase of more than 60 ms from baseline, and 69% and 7% of patients, respectively, had QTcF increases exceeding 450 ms and 500 ms. Patients treated with caprexa have experienced interstitial lung disease (ILD) or pneumonia, including cases of death. For patients presenting with nonspecific respiratory signs and symptoms, a diagnosis of ILD should be considered. Capresexa should be discontinued if acute or worsening pulmonary symptoms occur. If ILD is diagnosed, capresexa should be discontinued.
There have been reports of ischemic cerebrovascular events (sometimes fatal) associated with vandetanib treatment. In a phase 3 clinical trial, the incidence of ischemic cerebrovascular events was higher in the vandetanib group compared to the placebo group (1.3% vs. 0%); all ischemic cerebrovascular events reported in this study were grade 3. Vandetanib should be discontinued in patients experiencing a serious ischemic cerebrovascular event. The safety of restarting vandetanib treatment after resolution of an ischemic cerebrovascular event has not been investigated.
For more complete data on vandetanib warnings (out of 20), please visit the HSDB record page.

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Pharmacodynamics
Mean IC50 is approximately 2.1 μg/mL.

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1. Vandetanib has a dual antitumor mechanism: it inhibits VEGFR2 to suppress angiogenesis and blocks EGFR to suppress tumor cell proliferation, making it effective against both highly vascularized solid tumors and EGFR-driven malignancies[1][4].
2. Vandetanib is particularly effective against PTEN-deficient EGFR-mutant non-small cell lung cancer (NSCLC) cells, as PTEN deficiency activates the AKT signaling pathway (an alternative pathway to EGFR inhibitors), and vandetanib can simultaneously target EGFR and VEGFR2 to overcome this resistance[3].
3. Vandetanib is a substrate of the ABCG2 multidrug transporter, which may lead to resistance in ABCG2-overexpressing tumors; its combination with ABCG2 inhibitors can enhance their intracellular accumulation and efficacy[2].
4. In preclinical liver cancer models, vandetanib not only inhibits tumor growth but also enhances antitumor immunity by reducing myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment[4].

C22H24BRFN4O2

475.35

474.106

C, 55.59; H, 5.09; Br, 16.81; F, 4.00; N, 11.79; O, 6.73

443913-73-3

Vandetanib trifluoroacetate;338992-53-3;Vandetanib hydrochloride;524722-52-9;Vandetanib-d6;1174683-49-8;Vandetanib-d4;1215100-18-7

3081361

Light yellow to yellow solid powder

1.4±0.1 g/cm3

538.2±50.0 °C at 760 mmHg

240-243ºC

279.3±30.1 °C

0.0±1.4 mmHg at 25°C

1.629

5.51

1

7

6

30

539

0

BrC1C([H])=C([H])C(=C(C=1[H])F)N([H])C1C2=C([H])C(=C(C([H])=C2N=C([H])N=1)OC([H])([H])C1([H])C([H])([H])C([H])([H])N(C([H])([H])[H])C([H])([H])C1([H])[H])OC([H])([H])[H]

UHTHHESEBZOYNR-UHFFFAOYSA-N

InChI=1S/C22H24BrFN4O2/c1-28-7-5-14(6-8-28)12-30-21-11-19-16(10-20(21)29-2)22(26-13-25-19)27-18-4-3-15(23)9-17(18)24/h3-4,9-11,13-14H,5-8,12H2,1-2H3,(H,25,26,27)

N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-amine

ZD 6474; AZD-6474; ZD6474; AZD6474; CHEBI:38942; Vandetanib; ZD-6474; AZD 6474; Zactim; Caprelsa

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.26 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (5.26 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 3: 1% CMC Na: 30mg/mL

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 (Please use freshly prepared in vivo formulations for optimal results.)