Pazopanib

Pazopanib is an antineoplastic agent belonging to the pharmacological class of Tyrosine Kinase inhibitors, specifically Vascular Endothelial Growth Factor (VEGF) inhibitors.

The FDA approved Pazopanib for treating advanced renal cell cancer and advanced soft tissue sarcoma (STS) in patients with prior chemotherapy.

When pazopanib is administered, systemic exposure increases and meals enhance absorption. P-glycoprotein (Pgp) exhibits over 99% plasma protein binding, acting as a substrate in its distribution. With CYP1A2 and CYP2C8 having a minor role, the liver primarily metabolizes it through CYP3A4, and usually, elimination occurs through faeces, with less than 4% of it also being eliminated in urine.

The most common side effects of Pazopanib include diarrhoea, nausea/vomiting, headache, loss of appetite, weight loss, altered sense of taste, numbness/tingling/redness in hands/feet, or feeling tired/weak.

Pazopanib is available as an oral tablet.

The molecule is available in India, the United States, the United Kingdom, Australia, Germany, France, Canada, Japan, Brazil, China and Spain.

Pazopanib is an antineoplastic agent belonging to the pharmacological class of Tyrosine Kinase inhibitors, specifically Vascular Endothelial Growth Factor (VEGF) inhibitors.

Pazopanib is a multitargeted tyrosine kinase inhibitor of the second generation that inhibits the activity of c-kit, platelet-derived growth factor receptor-alpha, platelet-derived growth factor receptor-beta, and vascular endothelial growth factor receptor-1, -2, and -3. These receptor targets are a component of the angiogenesis pathway, which promotes the development of tumour blood vessels necessary for the survival and proliferation of tumours.

Pazopanib reaches its peak plasma time within 2 to 4 hours after administration.

Pazopanib achieves a peak plasma concentration of 58.1 mcg/mL.

The AUC (area under the curve) of Pazopanib is 1,037 hr•mcg/mL.

Pazopanib 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, usually on an empty stomach, at least 1-2 after or before meals.

• Advanced Renal Cell Carcinoma
• Soft Tissue Sarcomas

• In kidney cancer: Pazopanib is effective in treating kidney cancer and the symptoms that are related to it, such as blood in the urine, weight loss or low back discomfort that is not explained, exhaustion, appetite loss, etc. Focusing on several processes linked to tumour development and angiogenesis hinders the spread of cancer and inhibits cancer cells from proliferating. This prevents the cancer from spreading to other unaffected areas.
• Soft Tissue Sarcomas: Pazopanib, inhibiting cancer progression by targeting tumour cell proliferation and angiogenesis pathways, effectively enhances progression-free survival and overall survival rates for patients with advanced soft tissue sarcoma (STS).

Pazopanib is indicated in the following health conditions:

• For the treatment of adults with advanced renal cell carcinoma (RCC).
• In people with advanced soft tissue sarcoma (STS) who have undergone chemotherapy before, for therapeutic purposes.

Restriction on Use

Efficacy was not shown in gastrointestinal stromal tumours or adipocytic soft tissue sarcoma.

Orally: Administer without eating at least one hour before or two hours after meals if taken orally. It is advised not to chew or crush the medication as this increases the rates of absorption and bioavailability and may cause toxicity. Food also increases bioavailability, which might lead to even higher toxicity levels. Following these recommendations is essential to ensuring the best potential drug absorption and reducing the possibility of adverse effects.

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

Pazopanib is available as an oral tablet.

Dose Adjustment in Adult Patients:

Advanced Renal Cell Carcinoma (RCC)

On an empty stomach, take 800 mg PO daily (at least 1 hour AC or 2 hours PC).

Continue until the disease worsens or the toxicity becomes unacceptable.

Soft Tissue Sarcomas (STS)

On an empty stomach, 800 mg PO per day (at least 1 hour AC or 2 hours PC)

Continue until the disease worsens or the toxicity becomes unacceptable.

There aren't specific dietary restrictions; ensure regular meals. Consuming antioxidant-rich foods like berries, spinach, kidney beans, and dark chocolate is advisable to enhance the diet. Improve digestion by incorporating fibre-rich foods such as beans, peas, lentils, whole grains, nuts, and seeds. Eliminate smoking and alcohol consumption to promote overall health.

The dietary restriction should be individualized as per patient requirements.

• There have been reports of elevated bilirubin and serum transaminase levels, which can cause deadly hepatotoxicity. Before and during therapy, monitor the liver's enzymes.
• There may be torsades de pointes and lengthening of the QT interval. If a patient is more vulnerable, proceed with caution. Consider electrolytes and ECG monitoring in account.
• There have been reports of cardiac dysfunction, including congestive heart failure and a reduced left ventricular ejection fraction. Blood pressure should be tracked, hypertension should be treated quickly, and at-risk individuals' baseline and periodic left ventricular ejection fractions should be evaluated.
• Hemostasis, cerebral haemorrhage, or clinically substantial gastrointestinal bleeding are examples of fatal hemorrhagic episodes that have been documented. For individuals who have experienced such a history within the last six months, pazopanib is contraindicated.
• Potentially lethal arterial thrombotic episodes have been reported. Patients who are more susceptible to these occurrences proceed with care.
• It is possible to experience venous thrombotic events (VTE), which might include deadly pulmonary emboli (PE). Observe for signs of PE and VTE symptoms and indications.
• There have been instances of intestinal perforation or fistula, including fatal ones. When handling those who are vulnerable, use caution.
• There is a chance of Reversible Posterior Leukoencephalopathy Syndrome (RPLS). If RPLS signs or symptoms appear, stop taking pazopanib permanently.
• It has been noted that hypertension, including hypertensive crises, exists. Before starting pazopanib, blood pressure needs to be well managed. Observe periodically.
• It is advised that individuals undergoing surgery stop taking pazopanib.
• Hypothyroidism could happen. It is advised to continue to maintain vigilant tabs on thyroid function testing.
• Urine protein should be monitored if you have proteinuria. Stop medication if the urine protein level is greater than 3 grams in 24 hours and stop treatment altogether if the event occurs again, even with smaller doses.
• There have been reports of serious infections, some lethal. Monitor for symptoms and signs and treat any active infections immediately. Consider discontinuing pazopanib.
• Fetal damage can result from pazopanib. It is recommended that women who are fertile or may get pregnant while taking pazopanib be informed of the possible risks to the fetus.

It is not recommended during pregnancy as it may harm the unborn baby.

The adverse reactions related to Pazopanib can be categorized as:

• Common Adverse Effects: Diarrhea, hypertension, hair colour changes, nausea, fatigue, vomiting, and anorexia.
• Less Common Adverse Effects: Increased liver enzymes, abdominal pain, dysgeusia, headache, and stomatitis.
• Rare Adverse Effects: Hepatotoxicity, cardiac dysfunction, hypothyroidism, thrombotic events, reversible posterior leukoencephalopathy syndrome (RPLS), proteinuria, and severe infections

Reports on post-marketing

Polycythemia

Retinal tear or detachment

Arterial dissections, ruptures, and aneurysms (including aortic)

Pancreatitis

TLS (including fatal cases)

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

• Drug-Drug Interactions: Elevated levels of paclitaxel, midazolam, and dextromethorphan (metabolites) in the plasma. Elevated levels of uridine diphosphoglucuronosyl-transferase 1A1 (UGT1A1) substrates in the plasma, such as irinotecan. ALT levels elevated on using simvastatin. The use of QT-prolonging medications concurrently increases the risk of QT interval prolongation (e.g. haloperidol, lapatinib).

Potentially Fatal: Using pemetrexed and lapatinib at the same time increases the risk of toxicity (such as pulmonary or gastrointestinal haemorrhages) and/or fatality.

Potent CYP3A4 inhibitors (e.g., itraconazole, clarithromycin, atazanavir, nefazodone, lapatinib), P-gp, and BCRP all cause an increase in serum levels. Reduced serum levels using PPIs (like esomeprazole) and CYP3A4 inducers (like rifampin).

• Food Interaction: Increased exposure of the system to food. Avoid using it with grapefruit or grapefruit juice because it raises serum concentration when combined with meals. Serum concentration dropped when using St. John's wort.

The common side effects of Pazopanib include:

Acne

Dry skin

Nausea

Itching or rash on the skin

Vomiting

Diarrhea

Loss of appetite

Headache

Osteoarthritis (pain in the bones, muscles, or joints)

Fatigue

Change in colour of hair

Loss of weight

High blood pressure

Breathlessness

Weight loss

Taste change

Abnormal skin pigmentation

Hair discoloration

Tumor pain

• 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.

Pregnant women should be informed of the possible danger to their unborn child according to animal studies and the mechanism of action which suggests fetal damage.

There is no accessible data on drug usage in pregnant women to assess the risk linked with it.

Before beginning therapy, ascertain the status of pregnancy in potentially fertile females.

Contraception

For fertile women, use reliable contraception both throughout therapy and for at least two weeks following the final dosage.

Males with possible female partners for reproduction, including those who have undergone vasectomies: Throughout your therapy and for at least two weeks following your final dosage, use condoms.

Infertility

Fertility in males and females of reproductive capacity may be affected while undergoing therapy, according to results from research conducted on animals.

Animal data

Throughout organogenesis, oral administration of medication to pregnant rats and rabbits caused teratogenicity and abortion at systemic exposures lower than those reported at the MRHD of 800 mg/day (based on AUC) in animal developmental and reproductive toxicity investigations.

• Nursing Mothers

There is no information on the drug's presence or metabolites in human milk, their effects on nursing infants, or how much milk they produce.

Advise women not to breastfeed while undergoing therapy and for two weeks following the last dosage.

• Pediatric Use

As per the FDA, Pazopanib use in Pediatric patients has not been established.

Pazopanib may have detrimental effects on organ growth and maturation during the early postnatal stage of development, especially in infants under the age of two, according to its mode of action.

Dose Adjustment in Kidney Impairment Patients:

Mild-moderate-severe: No dose modification is necessary.

Dose Adjustment in Hepatic Impairment Patients:

There is no need to change the dose in mild cases (bilirubin <1.5x ULN and any ALT).

Moderate (any ALT and bilirubin ≥1.5–3 times ULN): Lower dosage: 200 mg PO qDay

Severe: Not recommended (bilirubin >3x ULN and any ALT).

The physician should be vigilant about the knowledge pertaining to the identification and treatment of overdosage of Pazopanib.

Signs and Symptoms

Overconsumption of Pazopanib may lead to Grade 3 fatigue and hypertension.

Management

There is no specific antidote or treatment for overdosage of Pazopanib. If recent ingestion occurs, employ gastric lavage or administer activated charcoal. Close monitoring of cardiac function, liver enzymes, electrolytes, and renal function is essential.

Maintain proper hydration, balance electrolytes, and manage symptoms like bleeding or wound complications. Mitigate adverse effects and ensure patient safety through close observation, supportive measures, and prompt intervention in cases of Pazopanib overdosage.

Pharmacodynamics

Pazopanib is a synthetic indazolylpyrimidine that reaches steady-state concentrations of >15 μg/ml. Patients undergoing treatment can observe a reduction in tumour blood flow, increased tumour apoptosis, inhibition of tumour growth, reduction in tumour interstitial fluid pressure, and hypoxia in cancer cells. Patients undergoing therapy may experience hypoxia in cancer cells, decreased tumour blood flow, increased tumour apoptosis, suppression of tumour development, and reduced tumour interstitial fluid pressure.

Pharmacokinetics

• Absorption: Pazopanib demonstrates increased systemic exposure when given with meals. When food is present, the maximum plasma concentration (Cmax) and the area under the curve (AUC) both rise by two times, and this effect increases if the tablet is crushed.
• Distribution: P-glycoprotein (Pgp) is influenced by the substrate Pazopanib, which changes the properties of Pgp's distribution. Furthermore, the medication has a strong affinity to plasma proteins—above 99%.
• Metabolism: Pazopanib is metabolized in the liver, primarily processed by the cytochrome P450 enzyme CYP3A4. CYP1A2 and CYP2C8 significantly facilitate the metabolism of it.
• Excretion: Pazopanib is primarily eliminated by the urine, with less than 4% being eliminated through the faeces, exhibiting an elimination half-life of approximately 31 hours.

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• https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022465s-010S-012lbl.pdf
• http://www.bccancer.bc.ca/drug-database-site/Drug Index/Pazopanib_monograph_1Oct2015.pdf
• https://www.ema.europa.eu/en/documents/product-information/votrient-epar-product-information_en.pdf
• https://www.ncbi.nlm.nih.gov/books/NBK548110/