Vandetanib

0.008

In water, 330 uM (pH 7.4); approx 650 uM (pH approx 6.5)

Vandetanib solid is found to be stable to both thermal and hydrolytic degradation but a small degree of degradation is observed under stressed photolytic conditions. In solution, vandetanib is degraded under acidic, oxidative and light stress conditions but it is stable under basic conditions.

Stable if stored as directed; avoid strong oxidizing agents

Danger

H302 (97.2%): Harmful if swallowed [Warning Acute toxicity, oral]；H360 (11.1%): May damage fertility or the unborn child [Danger Reproductive toxicity]；H360Df (80.6%): May damage the unborn child; Suspected of damaging fertility [Danger Reproductive toxicity]；H373 (97.2%): May causes damage to organs through prolonged or repeated exposure [Warning Specific target organ toxicity, repeated exposure]；H410 (97.2%): Very toxic to aquatic life with long lasting effects [Warning Hazardous to the aquatic environment, long-term hazard]

P203, P260, P264, P270, P273, P280, P301+P317, P318, P319, P330, P391, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 36 reports by companies from 7 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.；Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown. For more detailed information, please visit ECHA C&L website.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including vandetanib, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

Accidental release measures: ... Cordon off area of spill; wear self-contained breathing apparatus, protective clothing and heavy rubber gloves Measures for cleaning/collecting: absorb solutions with finely-powdered liquid-binding material (diatomite, universal binders); decontaminate surfaces and equipment by scrubbing with alcohol; dispose of contaminated material /in accordance with prevailing country, federal, state and local regulations/.

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

Handling should only be performed by personnel trained and familiar with handling of potent active pharmaceutical ingredients.

Information for safe handling: avoid inhalation and contact with skin, eyes and clothing ... .

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.

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).

EXPERIMENTAL: ... A significant distribution of radioactivity was seen in milk of lactating rats and further on in the plasma of suckling pups.

EXPERIMENTAL: In nonclinical studies, vandetanib was excreted in rat milk and found in plasma of pups following dosing to lactating rats. Vandetanib transfer in breast milk resulted in relatively constant exposure in pups due to the long half-life of the drug.

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 the

/SIGNS AND SYMPTOMS/ 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.

/SIGNS AND SYMPTOMS/ 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.

/SIGNS AND SYMPTOMS/ 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.

/SIGNS AND SYMPTOMS/ Serious hemorrhagic events, sometimes fatal, have been reported with vandetanib. Vandetanib should not be used in patients with a recent history of hemoptysis (2.5 mL of red blood or more). Vandetanib should be discontinued in patients with severe hemorrhage.

For more Human Toxicity Excerpts (Complete) data for Vandetanib (14 total), please visit the HSDB record page.

Drug Induced Liver Injury Rank (DILIrank 2.0)

Vandetanib

Ambiguous-DILI-concern

3

Adverse reactions

DOI:10.1016/j.drudis.2016.02.015

/LABORATORY ANIMALS: Acute Exposure/ 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. 1000 mg/kg in rats corresponds to a dose of 6000 mg/sq m, which is approximately 30 times the recommended daily dose for a 70 kg patient.

/LABORATORY ANIMALS: Acute Exposure/ 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.

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ Dose-limiting toxicities in 1, 6 and 9 month studies included (variously across the studies) gastrointestinal effects in dogs (including loose/abnormal feces, emesis and body weight loss), and skin and hepatotoxicity in rats. The morbidity and mortality associated with these key findings at the initial high doses resulted in either dose reduction (high dose reduced from 20 mg/kg/day to 10 mg/kg/day from Week 13 of the 6 month rat, and the 20 mg/kg/day top dose of the 9 month dog study was reduced to 15 mg/kg/day in Week 17) or the early cessation of dosing of the high dose groups of the 1 month rat study (Day 25) and the 1 month dog study (Day 15). In the 6 month rat study, the unscheduled deaths of several animals in the 20 mg/kg/day group were attributed in part to acute cholangitis and/or pancreatitis. However, these findings were not present following subsequent dose reduction from 20 mg/kg/day to 10 mg/kg/day. Elevated ALT and AST activities were found in some rats receiving 5 or 25 mg/kg/day for 1 month or 20/10 mg/kg/day for 6 months without histopathological correlate. Hepatobiliary changes were not seen in the 1 or 9 month dog studies. In the four week period after cessation of dosing in the one month rat study, dysplasia of incisor teeth was observed in animals previously given 75 mg/kg/day, and similar changes were seen in several decedents at 20/10 mg/kg/day in the 6 month rat study. Daily oral dosing of vandetanib for 1 month resulted in a dose-related, reversible dysplasia of the epiphyseal growth plates of the femorotibial joint in rats dosed at 25 or 75 mg/kg/day and in the femur of dogs dosed at 40 mg/kg/day. Renal papillary necrosis was observed in rats dosed orally for 1 month at 25 or 75 mg/kg/day and was still present at the end of the 4 week recovery period. Renal papillary necrosis was not seen in the 6 month rat study or in any dog study. Histopathological and/or ultrastructural changes

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ In the embryofetal development study in rats, heart vessel abnormalities (aortic arch interrupted or right sided, subclavian artery arising from ductus arteriosus or pulmonary arch; subclavian artery retro-oesophageal; innominate artery absent) and precocious ossification of some skull bones were observed at 25 mg/kg/day. Heart vessel abnormalities were observed also at lower doses (10 mg/kg/day and 1 mg/kg/day) and a no-effect level was not established.

For more Non-Human Toxicity Excerpts (Complete) data for Vandetanib (9 total), please visit the HSDB record page.

Vandetanib may cause fetal harm if administered to pregnant women; the drug has been shown to be embryotoxic, fetotoxic, and teratogenic in animals. Pregnancy should be avoided during therapy.

Vandetanib should not be initiated in patients with QT interval (corrected for heart rate using Fridericia's formula (QTcF) exceeding 450 msec. The drug 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 administration of vandetanib.

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/

/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/

/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

In the event of an overdose, monitor patients closely for QTc prolongation. Because of the 19-day half-life, adverse reactions may not resolve quickly.

For more Antidote and Emergency Treatment (Complete) data for Vandetanib (7 total), please visit the HSDB record page.

◉ 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.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including vandetanib, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

L - Antineoplastic and immunomodulating agents；L01 - Antineoplastic agents；L01E - Protein kinase inhibitors；L01EX - Other protein kinase inhibitors；L01EX04 - Vandetanib

QL - Antineoplastic and immunomodulating agents；QL01 - Antineoplastic agents；QL01E - Protein kinase inhibitors；QL01EX - Other protein kinase inhibitors；QL01EX04 - Vandetanib

ZD-6474 is a potent and selective inhibitor of VEGFR (vascular endothelial growth factor receptor), EGFR (epidermal growth factor receptor) and RET (REarranged during Transfection) tyrosine kinases. VEGFR- and EGFR-dependent signalling are both clinically validated pathways in cancer, including non-small-cell lung cancer (NSCLC). RET activity is important in some types of thyroid cancer, and early data with vandetanib in medullary thyroid cancer has led to orphan-drug designation by the regulatory authorities in the USA and EU.

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 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.

Oncogenic conversion of the RET /rearranged during transfection/ tyrosine kinase is a frequent feature of medullary thyroid carcinoma (MTC). Vandetanib is an ATP-competitive inhibitor of RET, epidermal growth factor receptor (EGFR), and vascular endothelial growth factor receptors kinases. In this study, vandetanib mechanism of action in TT and MZ-CRC-1 human MTC cell lines, carrying cysteine 634 to tryptophan (C634W) and methionine 918 to threonine (M918T) RET mutation respectively /were studied/. Vandetanib blunted MTC cell proliferation and RET, Shc and p44/p42 mitogen-activated protein kinase (MAPK) phosphorylation. Single receptor knockdown by RNA interference showed that MTC cells depended on RET for proliferation. Adoptive expression of the vandetanib-resistant V804M RET mutant rescued proliferation of TT cells under vandetanib treatment, showing that RET is a key vandetanib target in these MTC cells. Upon RET inhibition, adoptive stimulation of EGFR partially rescued TT cell proliferation, MAPK signaling, and expression of cell-cycle-related genes. This suggests that simultaneous inhibition of RET and EGFR by vandetanib may overcome the risk of MTC cells to escape from RET blockade through compensatory over-activation of EGFR.

Rearranged during transfection (RET) is widely expressed in neuroblastoma (NB) and partly contributes to high metastatic potential and survival of NB. The aim of the present study was to investigate whether vandetanib (a RET inhibitor) inhibits proliferation, migration and invasion of NB cells in vitro. The effects of vandetanib on the proliferation, apoptosis and cell cycle and on RET phosphorylation of SK-N-SH and SH-SY5Y cells were evaluated in vitro. The migration and invasion potential of vandetanib-treated NB cells were analyzed using Transwell cell migration and invasion assays, respectively. qPCR, western blotting and immunofluorescence were used to detect mRNA and protein levels in NB cells treated with vandetanib. Our data demonstrated that vandetanib inhibits the proliferation of SK-N-SH and SH-SY5Y cells and that this inhibition is mediated by the induction of G1 phase cell cycle arrest at lower concentrations and by apoptosis at higher concentrations. In the presence of vandetanib, the migration and invasion of two NB cell lines were markedly decreased compared with the control group (p<0.01). In addition, our data showed that the levels of C-X-C chemokine receptor type 4 (CXCR4) and matrix metalloproteinase 14 (MMP14) mRNA expression in NB cell lines treated with vandetanib were significantly lower than those in the cells that were treated with vehicle (p<0.01) and similar results were obtained for protein levels as determined by western blotting and immunofluorescence analysis. Vandetanib may inhibit the proliferation, migration and invasion of NB cells in vitro. The potential mechanisms for the inhibition of NB migration and invasion by vandetanib may partly be attributed to the ability of vandetanib to suppress the expression of CXCR4 and MMP14 in human NB cells.

For more Mechanism of Action (Complete) data for Vandetanib (6 total), please visit the HSDB record page.

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. ...

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.

YO460OQ37K

VANDETANIB

Established Pharmacologic Class [EPC] - Kinase Inhibitor

Mechanisms of Action [MoA] - Protein Kinase Inhibitors

Vandetanib is a Kinase Inhibitor. The mechanism of action of vandetanib is as a Protein Kinase Inhibitor.

YO460OQ37K

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.

Antineoplastic

MEDICATION