VEGFR2 (IC50 = 40 nM); VEGFR3 (IC50 = 110 nM); EGFR/HER1 (IC50 = 500 nM)

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.

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.

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).

Absorption, Distribution and Excretion
Slow- peak plasma concentrations reached at a median 6 hours. On multiple dosing, Vandetanib accumulates about 8 fold with steady state reached after around 3 months.
About 69% was recovered following 21 days after a single dose of vandentanib. 44% was found in feces and 25% in urine.
Vd of about 7450 L.
Vandetanib binds to human serum albumin and a1-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%.
Within a 21-day collection period after a single dose of (14)C-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 ug/mL. This is higher than vandetanib plasma concentrations (0.81 ug/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.
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.
The protein binding of (14)C-Vandetanib in plasma of mice, rats, rabbits dogs and human was moderate, from 83 to 90%. The tissue distribution of vandetanib and/or metabolites in pigmented and non pigmented male rats after single oral dosing was slow but extensive, and consistent with the distribution pattern of a lipophilic compound. Highest concentrations of vandetanib and/or its metabolites were seen in the majority of tissues at 6-8 hours after administration. The distribution of radioactivity to brain was evident. Retention of radioactivity was seen in pigmented tissues indicating melanin affinity. A significant distribution of radioactivity was seen in milk of lactating rats and further on in the plasma of suckling pups.
For more Absorption, Distribution and Excretion (Complete) data for Vandetanib (8 total), please visit the HSDB record page.

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Metabolism / Metabolites
Unchanged vandentanib and metabolites vandetanib N-oxide and N-desmethyl vandetanib were detected in plasma, urine and feces. N-desmethyl-vandetanib is primarily produced by CYP3A4, and vandetanib-N-oxide is primarily produced by flavin–containing monooxygenase enzymes FMO1 and FMO3.
The metabolism of vandetanib seemed to be similar in the toxicology species, rat and dog, as well as in mouse and human. The 2 major metabolites identified in excreta, were N-desmethyl-vandetanib and vandetanib-N-oxide. In mouse, a minor metabolite was also identified as O-desalkyl-vandetanib glucuronid. A glucuronide conjugate was also detected in human urine. Metabolism as well as biliary excretion appears to be most important for the elimination of vandetanib in preclinical species. CYP identification studies in vitro, suggest that CYP3A4 is involved in the formation of N-desmethyl-Vandetanib. vandetanib-N-oxide is formed via FMO1 and FMO3 (FMO=flavine mono-oxygenase). Both these enzymes are also found in kidney indicating that renal excretion might be contributed to the clearance of vandetanib.
Following oral dosing of (14)C-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-desmethyl-vandetanib and vandetanib-N-oxide circulate at concentrations of approximately 7-17% and 1.4-2.2%, respectively, of those of vandetanib.
... In plasma, concentrations of total radioactivity were higher than vandetanib concentrations at all time points, indicating the presence of circulating metabolites. Unchanged vandetanib and 2 anticipated metabolites (N-desmethylvandetanib and vandetanib N-oxide) were detected in plasma, urine, and feces. A further trace minor metabolite (glucuronide conjugate) was found in urine and feces. ... Unchanged vandetanib and N-desmethyl and N-oxide metabolites were detected in plasma, urine, and feces.

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Biological Half-Life
Median half life of 19 days.
... Caprelsa at the 300 mg dose in medullary thyroid cancer (MTC) patients /is/ characterized by a ... median plasma half-life of 19 days.
... Vandetanib was absorbed and eliminated slowly with a half life of approximately 10 days after single oral doses. ...

Toxicity Summary
IDENTIFICATION AND USE: Vandetanib is a white to off white powder that is formulated into film-coated tablets. Vandetanib is a multitargeted tyrosine kinase inhibitor used for the treatment of symptomatic or progressive medullary thyroid cancer in patients with unresectable locally advanced or metastatic disease. Because of the risk of QT prolongation, torsades de pointes, and sudden death, the US Food and Drug Administration (FDA) requires a Risk Evaluation and Mitigation Strategy (REMS) for vandetanib. Under the terms of the REMS program, vandetanib is available only under a restricted distribution program. It was granted orphan drug status by the FDA. HUMAN EXPOSURE AND TOXICITY: Vandetanib prolongs the QT interval in a concentration-dependent manner. Torsades de pointes (a distinctive polymorphic ventricular tachycardia in which the QRS amplitude varies and the QRS complexes appear to twist around), ventricular tachycardia, and sudden death have all been reported in patients receiving vandetanib. Vandetanib should not be used in patients who have a history of torsades de pointes, congenital long QT syndrome, bradyarrhythmias, or uncompensated heart failure, or in patients with electrolyte disturbances. Hypocalcemia, hypokalemia, and/or hypomagnesemia must be corrected prior to the administration of vandetanib. Other toxicities that are associated with the use of vandetanib and have resulted in fatalities include: severe skin reactions (including Stevens-Johnson syndrome), interstitial lung disease or pneumonitis, ischemic cerebrovascular events, serious hemorrhagic events and heart failure. Vandetanib may also cause fetal harm if administered to pregnant women. Pregnancy should therefore be avoided during vandetanib therapy. Vandetanib was not clastogenic to cultured human lymphocytes. ANIMAL STUDIES: In the rat, a single oral dose at 2000 mg/kg was not tolerated and all animals died or were killed for humane reasons by Day 4. Histopathological findings in these rats included hepatocyte vacuolation, fat deposition and necrosis in the liver, ulceration in the stomach, mucosal single cell necrosis and erosion in the duodenum, and macrophage vacuolation in the spleen. There were no adverse effects in rats dosed at 1000 mg/kg. A single oral dose of vandetanib at 2000 mg/kg to mice was not tolerated and all animals died or were killed for humane reasons on Day 1. A single oral dose of 1000 mg/kg resulted in the death of 1 out of 10 mice. There were no salient histopathology findings except for ulceration in the stomach in 1 animal dosed at 2000 mg/kg. In 1, 6 and 9 month studies, the dose limiting toxicities included gastrointestinal effects in dogs (including loose/abnormal feces, emesis and body weight loss), and skin toxicity and hepatotoxicity in rats. Vandetanib had no effect on copulation or fertility in male rats, while in female rats there was a trend towards increased estrus cycle irregularity, a slight reduction in pregnancy and an increase in post-implantation loss. In rats, vandetanib demonstrated the potential to cause embryo-fetal loss, delayed fetal 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 showed no mutagenic potential in 4 strains of Salmonella typhimurium (TA1535, TA1537, TA98 and TA100) and 2 strains of Escherichia coli (WP2P and WP2 uvrA) with or without metabolic activation.

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Hepatotoxicity
In large clinical trials of vandetanib, abnormalities in routine liver tests were common with serum aminotransferase elevations, occurring in up to half of patients and rising above 5 times the upper limit of normal (ULN) 2% to 5% of patients. In prelicensure trials of vandetanib in thyroid cancer, there were no reports of clinically apparent liver injury with jaundice or hepatic failure. Since approval and more wide scale use, there have been no published reports of hepatotoxicity due to vandetanib and the product label does not include discussion of hepatotoxicity. However, many of the kinase inhibitors used in cancer chemotherapy have been implicated in cases of clinically apparent liver injury which typically arises within the first 2 to 12 weeks of therapy, presenting with symptoms of fatigue, nausea and jaundice and a hepatocellular pattern of serum enzyme elevations without immunoallergic or autoimmune features. Several tyrosine kinase inhibitors (imatinib, nilotinib) have also been implicated in causing reactivation of hepatitis B.
Likelihood score: E* (unproven but suspected rare cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No information is available on the clinical use of vandetanib during breastfeeding. Because vandetanib is 90% bound to plasma proteins, the amount in milk is likely to be low. However, its half-life is 19 days and it might accumulate in the infant. The manufacturer recommends that breastfeeding be discontinued during vandetanib therapy and for 4 months after the last dose.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
Protein binding of about 90%.

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Interactions
Concomitant use of vandetanib with drugs known to prolong the QT interval, including class Ia (e.g., disopyramide, procainamide, quinidine) and class III (e.g., amiodarone, sotalol, dofetilide) antiarrhythmic agents, some anti-infectives (e.g., clarithromycin, gatifloxacin, moxifloxacin), some antipsychotic agents (e.g., chlorpromazine, thioridazine, haloperidol, asenapine, olanzapine, paliperidone, pimozide, quetiapine, ziprasidone), some type 3 serotonin (5-HT3) receptor antagonists used as antiemetic agents (e.g., dolasetron, granisetron, ondansetron), chloroquine, methadone, and tetrabenazine should be avoided. If a drug known to prolong the QT interval must be administered, more frequent ECG monitoring is recommended. If a 5-HT3 receptor antagonist is clinically necessary, some clinicians prefer granisetron because its effects on ECG intervals are less pronounced than those observed with dolasetron or ondansetron.
Inducers of CYP3A4 can alter plasma vandetanib concentrations. Concomitant use of vandetanib with potent CYP3A4 inducers (e.g., carbamazepine, dexamethasone, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine) should be avoided. St. John's wort (Hypericum perforatum) may unpredictably decrease vandetanib exposure, and concomitant use of vandetanib with this agent also should be avoided.
Caprelsa increased plasma concentrations of digoxin. Use caution and closely monitor for toxicities when administering Caprelsa with digoxin.
Capresla increased plasma concentrations of metformin that is transported by the organic cation transporter type 2 (OCT2). Use caution and closely monitor for toxicities when administering Capresla with drugs that are transported by OCT2.

[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
Antineoplastic
Caprelsa is a kinase inhibitor indicated for the treatment of symptomatic or progressive medullary thyroid cancer in patients with unresectable locally advanced or metastatic disease. /Incuded in US product label/
Because of the risk of QT prolongation, torsades de pointes, and sudden death, the US Food and Drug Administration (FDA) required and has approved a Risk Evaluation and Mitigation Strategy (REMS) for vandetanib. Under the terms of the REMS program, vandetanib is available only under a restricted distribution program (Caprelsa REMS Program). Prescribers and pharmacies must be certified with the Caprelsa REMS Program before they can prescribe or dispense vandetanib. To be certified, prescribers must review the educational materials, agree to comply with the REMS requirements, and enroll in the program. Pharmacies that dispense vandetanib must enroll in the program, train their pharmacy staff to verify that each prescription is written by a certified prescriber before dispensing the drug to the patient, and agree to comply with the REMS requirements.
Vandetanib is used for the treatment of symptomatic or progressive medullary thyroid cancer in patients with unresectable locally advanced or metastatic disease; vandetanib is designated an orphan drug by the US Food and Drug Administration (FDA) for the treatment of this cancer.

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Drug Warnings
/BOXED WARNING/ WARNING: QT PROLONGATION, TORSADES DE POINTES, AND SUDDEN DEATH. Caprelsa can prolong the QT interval. Torsades de pointes and sudden death have occurred in patients receiving Caprelsa. Do not use Caprelsa in patients with hypocalcemia, hypokalemia, hypomagnesemia, or long QT syndrome. Correct hypocalcemia, hypokalemia and/or hypomagnesemia prior to Caprelsa administration. Monitor electrolytes periodically. Avoid drugs known to prolong the QT interval. Only prescribers and pharmacies certified with the restricted distribution program are able to prescribe and dispense Caprelsa.
Vandetanib prolongs the QT interval in a concentration-dependent manner. Torsades de pointes, ventricular tachycardia, and sudden death have been reported in patients receiving vandetanib. In the phase 3 clinical study, patients randomized to receive vandetanib (300 once daily) had a mean increase in the QT interval (corrected for heart rate using Fridericia's formula (QTcF)) of 35 msec (range: 33-36 msec) from baseline; this increase in QTcF remained above 30 msec for the duration of the study (up to 2 years). In addition, an increase in QTcF of more than 60 msec from baseline occurred in 36% of patients receiving vandetanib, and QTcF exceeded 450 msec or 500 msec in 69 or 7% of patients, respectively.
Interstitial Lung Disease (ILD) or pneumonitis, including fatalities, has occurred in patients treated with Caprelsa. Consider a diagnosis of ILD in patients presenting with non-specific respiratory signs and symptoms. Interrupt Caprelsa for acute or worsening pulmonary symptoms. Discontinue Caprelsa if ILD is confirmed.
Ischemic cerebrovascular events, sometimes fatal, have been reported with vandetanib. In the phase 3 clinical study, ischemic cerebrovascular events were observed more frequently with vandetanib compared with placebo (1.3 versus 0%); all ischemic cerebrovascular events reported in this study were grade 3. Vandetanib should be discontinued in patients who experience a severe ischemic cerebrovascular event. The safety of resumption of vandetanib therapy after resolution of an ischemic cerebrovascular event has not been studied.
For more Drug Warnings (Complete) data for Vandetanib (20 total), please visit the HSDB record page.

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Pharmacodynamics
Mean IC50 of approximately 2.1 μg/mL.

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.)