Vandetanib

Vandetanib is an antineoplastic agent belonging to the pharmacological class of Epidermal Growth Factor Receptor (EGFR) inhibitors.

The FDA approved Vandetanib for treating advanced medullary thyroid cancer.

After being administered, Vandetanib is gradually absorbed by the body, displaying a broad distribution volume of around 7,450 litres. It binds primarily to albumin and α1-acid glycoprotein (about 90%) in plasma proteins. The liver activates the CYP3A4 enzyme to primarily metabolize vandetanib. Faeces account for approximately 44% of vandetanib excretion, and urine accounts for approximately 25%.

The most common side effects of Vandetanib include nausea, decreased appetite, changes in taste, dry mouth, stomach pain, vomiting, diarrhea, headache, or blurred vision.

Vandetanib is available as an oral tablet.

The molecule is available in India, the United States, Canada, countries within the European Union, Australia, Japan and South Korea.

Vandetanib is an antineoplastic agent belonging to the pharmacological class of Epidermal Growth Factor Receptor (EGFR) inhibitors.

Vandetanib is a potent, oral, selective inhibitor of many tyrosine kinases, including EGFR, RET receptor tyrosine kinases, and vascular endothelial growth factor receptor-2 (VEGFR-2). Vandetanib decreases tumour development and metastasis in vivo while reducing angiogenesis generated by tumour cells and tumour vascular permeability.

Vandetanib reaches peak plasma time at 6 hours, ranging from 4 to 10 hours.

Vandetanib achieves a steady state after approximately three months of continuous dosing, exhibiting an approximately 8-fold accumulation with repeated administrations.

Vandetanib is available as an oral tablet.

Tablets: To be swallowed whole with water/liquid. Do not chew, crush or break it.

The physician recommends taking this medication orally once daily, with or without meals.

Treatment of Thyroid cancer: The thyroid, which is shaped like a butterfly and is located at the base of your neck, is responsible for producing hormones that control your body temperature, heart rate, blood pressure, and weight. Thyroid cancer might appear asymptomatic at first and develop inside thyroid cells. By actively limiting the oxygen available to cancer cells, vandetanib stops the development of these cells and prevents them from spreading. Vandetanib targets specific receptors to limit the development of cancer cells. Vandetanib is an essential medication that helps manage cancer by actively blocking signalling pathways critical to tumour growth.

For the treatment of symptomatic or progressing medullary thyroid carcinoma in individuals with incurable, locally advanced or metastatic illness, venetanib is indicated.

Orally: Patients orally administer Vandetanib by swallowing tablets once daily with water or without food. They must swallow the tablet whole, avoiding chewing or crushing. If swallowing is challenging, disperse the tablet in half a glass of plain, non-carbonated water, stirring for about 10 minutes. No other liquid is permissible. After dispersion, immediately swallow and mix any remaining residue with half a glass of water, swallowing again. Liquid dispersion is suitable for administration through nasogastric or gastrostomy tubes. In case of a missed dose, if less than 12 hours from the next dose, take it regularly; if over 12 hours, take the missed dose and the next scheduled dose.

The dosage and duration of treatment should be as per the treating physician's clinical judgment.

Vandetanib is available as an oral tablet.

Dose Adjustment in Adult Patients:

Cancer of the Medullary Thyroid.

300 mg every day, either with or without meals

continued until the disease worsens or there is intolerable toxicity.

Considerations for Dosage

Monitor QT interval prolongation and other side effects cautiously since they cannot completely disappear until the medication has had three plasma half-lives.

While on Vandetanib, avoid grapefruit or its juice to prevent potential drug metabolism issues. Beware of medications, supplements, or herbal products that may interact with Vandetanib. No specific dietary restrictions exist, so maintain regular meals, emphasizing adequate hydration.

The dietary restriction should be individualized as per patient requirements.

• Individuals with known hypersensitivity or allergic reactions to this medication or its components.
• Patients with congenital long QT syndrome.
• Pregnancy and lactation.

• While using vandetanib, maintain a close watch on your ECG and your blood potassium, calcium, magnesium, and TSH levels. To address potential concerns related to longer QT intervals and the potential for Torsades de Pointes, which can result in sudden death, the dosage of vandetanib should be adjusted as needed.
• Be cautious of severe skin reactions, such as Stevens-Johnson syndrome, and consider stopping Vandetanib.
• Examine carefully any unexplained non-specific respiratory symptoms and indications. If verified, stop using Vandetanib for ILD as soon as possible. Given the potential severity of this illness, particularly the deaths linked to interstitial lung disease, recognition and care are essential.
• It is essential to think about stopping or interrupting Vandetanib if one experiences diarrhoea, heart failure, ischemic cerebrovascular episodes, hypertension, or reversible posterior leukoencephalopathy syndrome. For patient safety, these possible issues must be resolved as soon as possible.
• A developing fetus may be harmed by vandetanib, and there is a danger of toxicity to the embryo. When using vandetanib and for four months after stopping therapy, women should be well informed about the possible risks and strongly recommended not to become pregnant. To reduce the possibility of potential damage to the developing fetus, detailed counselling on contraceptive methods is crucial.

The adverse reactions related to Vandetanib can be categorized as:

• Common Adverse Effects: Nausea, diarrhea, rash, hypertension, photosensitivity reaction.
• Less Common Adverse Effects: Fatigue, headache, pruritus, hypocalcemia or anorexia.
• Rare Adverse Effects: Pancreatitis, heart failure, Hypomagnesemia (Grade 3 or 4)

Neutropenia (Grade 3 or 4), Interstitial lung disease or severe skin reactions like Stevens-Johnson syndrome.

Reports on Postmarketing

Renal failure

Wound healing

The clinically relevant drug interactions of Vandetanib are briefly summarized here.

Potent CYP3A4 inducers, such as dexamethasone, carbamazepine, phenytoin, phenobarbital, rifabutin, and rifampicin, cause a decrease in plasma levels. Increased digoxin and metformin plasma concentrations.

Potentially Fatal: Drugs that extend the QTc interval, such as mizolastine, moxifloxacin, cisapride, arsenic, erythromycin IV, and toremifene, as well as antiarrhythmic medications including amiodarone, disopyramide, dofetilide, procainamide, and sotalol, increase the risk of torsades de pointes.

The common side effects of Vandetanib include:

• Skin and cutaneous disorders
• Elevated blood pressure
• Increased QT interval
• Lower blood calcium level
• Reduced appetite
• Protein in urine
• Gastrointestinal disturbance
• Reduced thyroid hormone levels
• Muscle spasm

• Pregnancy

Pregnancy Category D (FDA): Use in cases where no safer medication is available, and life is in danger. Positive evidence of prenatal risk in humans.

Due to the drug's embryotoxic and fetotoxic properties, treatment may damage a fetus when given to a pregnant woman.

Animal data

Drug-induced fetal abnormalities in rats at doses lower than or equivalent to those anticipated at the 300 mg/day approved human dose; advise expectant mothers of possible fetal risk.

Reproductive potential

When given to a pregnant woman, therapy can damage the fetus; thus, it is advised that women who are capable of becoming pregnant use effective contraception during treatment and for four months following the last dosage.

Animal research suggests that treatment can reduce both male and female fertility, while data on the impact on human fertility are lacking.

• Nursing Mothers

The drug was found in the milk of nursing rats. However, there are no data on its presence in human milk or its metabolites, effects on breastfed children, or effects on milk production. It is advised that mothers refrain from breastfeeding throughout therapy and for four months following the last dosage due to the possibility of significant adverse effects in breastfed infants.

Animal data

Drug transfer in breast milk resulted in relatively continual exposure in pups due to the extended half-life of the drug; in nonclinical tests, the drug was excreted in rat milk and identified in pups' plasma after dosing to nursing rats.

• Pediatric Use

As per the FDA, the safety and efficacy of Vandetanib have not been specifically studied in pediatric patients.

• Geriatric Use

For older people, there is no need to modify the initial dose. Vandetanib has little clinical evidence when used in individuals with MTC who are older than 75.

Dose Adjustment in Kidney Impairment Patients:

CrCl ≥50 mL/min: No dose modification is required.

Moderate: Lower the initial dosage to 200 mg PO qDay (CrCl 30 to <50 mL/min).

Severe (CrCl less than 30 mL/min): Not advised.

Dose Adjustment in Hepatic Impairment Patients:

Mild (Child-Pugh A): Dose adjustment is not determined.

Severe to moderate (Child-Pugh B or C): not recommended.

Pharmacodynamics

Electrophysiology of the Heart

In the phase 3 clinical study, 231 patients with medullary thyroid carcinoma were randomized to receive 300 mg of CAPRELSA once a day. QT prolongation reliant on sustained plasma concentration has been linked to CAPRELSA. For the 300 mg dosage, the mean (90% CI) QTcF change from baseline (ΔQTcF) was 35 (33-36) ms, according to the exposure-response relationship. Throughout the study, which lasted for up to two years, the ΔQTcF stayed over 30 ms. Furthermore, ΔQTcF increased in more than 60 ms for 36 per cent of patients, and QTcF increased in more than 500 ms for 4.3% of patients. There have been reports of sudden death and Torsades de pointes.

Pharmacokinetics

• Absorption: When administered, vandetanib enters the body and is slowly absorbed.
• Distribution: Vandetanib binds to plasma proteins with a strong affinity for albumin and α1-acid glycoprotein at an estimated rate of 90%. Its vast volume of distribution is 7,450 L.
• Metabolism: The liver actively participates in Vandetanib metabolism. Vandetanib-N-oxide is formed by the flavin-containing mono-oxygenase enzymes FMO1 and FMO3, while CYP3A4 helps convert to N-desmethyl vandetanib.
• Excretion: Feces (about 44%) and urine (approximately 25%) are the primary methods by which Vandetanib is eliminated from the body. Vandetanib exhibits a long elimination half-life, up to almost 19 days.

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• https://www.ncbi.nlm.nih.gov/books/NBK548169/
• https://www.ema.europa.eu/en/documents/product-information/caprelsa-epar-product-information_en.pdf
• https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022405s007lbl.pdf
• http://www.bccancer.bc.ca/drug-database-site/Drug Index/Vandetanib_monograph.pdf