Axitinib

Axitinib is an antineoplastic agent belonging to the pharmacological class of tyrosine kinase inhibitors.

The FDA approved Axitinib for treating advanced renal cell carcinoma (RCC)which is a type of kidney cancer.

Axitinib rapidly absorbs from the gastrointestinal tract with approximately 58% bioavailability. It extensively distributes (volume: 160 L) and binds strongly to plasma proteins (>99%). Hepatic metabolism and elimination through faeces (41%, 12% unchanged) and urine (23%) occur.

The most common side effects of Axitinib include joint pain, high blood pressure and loss of appetite.

Axitinib 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.

Axitinib is an antineoplastic agent belonging to the pharmacological class of tyrosine kinase inhibitors.

At therapeutic plasma concentrations, Axitinib actively inhibits receptor tyrosine kinases, specifically VEGFR-1, VEGFR-2, and VEGFR-3. These receptors are essential for the growth of tumours, the progression of cancer, and pathological angiogenesis. In vitro and mouse models, axitinib inhibits the proliferation and survival of endothelial cells mediated by VEGF. Axitinib has been shown to suppress tumour growth and VEGFR-2 phosphorylation in tumour xenograft mouse models.

Axitinib reaches its peak plasma concentration within 2.5 to 4.1 hours after administration.

The peak plasma concentration of axitinib reaches 27.8 ng/mL after administration.

The AUC of axitinib is 265 ng•h/mL after administration.

Axitinib 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 twice daily, with or without food.

Orally: Administer the medication twice daily, approximately 12 hours apart. The tablet can be taken with or without food. Swallow the tablet whole with a glass of water, and do not split, crush, or chew it. If a dose is missed or if the patient vomits, an additional dose should not be taken. Instead, the next prescribed dose should be taken at the usual time.

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

Axitinib is available as an oral tablet.

Initially, 5 mg PO BID

Avelumab 800 mg IV every two weeks in addition to Axitinib 5 mg PO BID

Continue until the disease worsens or the toxicity becomes intolerable.

When using nivolumab in combination therapy, think about increasing the dose of axitinib beyond 5 mg/dose over two weeks or more.

Axitinib 5 mg PO BID in addition to Pembrolizumab 200 mg IV every three weeks or 400 mg IV every six weeks

Continue until the disease worsens or the toxicity becomes intolerable.

When using pembrolizumab in combination therapy, you may want to consider increasing the dose of axitinib beyond 5 mg once every six weeks or more.

Avoid consuming grapefruit or its juice with Axitinib to prevent potential drug metabolism issues. No specific dietary restrictions exist; incorporate antioxidant-rich foods like berries and spinach. Include fibre-rich foods such as beans, peas, lentils, whole grains, nuts, and seeds for improved digestion. Refrain from smoking and alcohol consumption during Axitinib treatment.

The dietary restriction should be individualized as per patient requirements.

The adverse reactions related to Axitinib can be categorized as:

Vascular conditions: Ruptures, dissections, and aneurysms of the arteries, including the aorta

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

Axitinib and potent CYP3A4/5 inhibitors, like ketoconazole, shouldn't be administered together to avoid increased plasma exposure. Avoiding grapefruit or juice is also necessary, as it can increase axitinib concentrations. Choosing drugs with low potential to inhibit CYP3A4/5 is advised. If co-administering potent CYP3A4/5 inhibitors, lowering the dose of axitinib is recommended. A similar caution is necessary for co-administration of strong CYP3A4/5 inducers such as St. John's wort, carbamazepine, rifampin, dexamethasone, phenytoin, rifabutin, and rifapentine. Take concurrent drugs that have a low potential for CYP3A4/5 activation. Avoid using bosentan, efavirenz, etravirine, modafinil, and nafcillin, as they are moderate CYP3A4/5 inducers that may also lessen exposure to axitinib.

The common side effects of Axitinib include:

Diarrhea

Hypertension

Fatigue

Decreased appetite

Nausea

Dysphonia

Palmar-plantar erythrodysesthesia syndrome

Weight decreased

Vomiting

Asthenia

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.

There is no human data available to inform drug-associated risk. Axitinib was found to be teratogenic, embryotoxic, and fetotoxic in developmental toxicity studies in mice at maternal exposures that were lesser than human exposures at recommended clinical doses. These findings, along with the drug's mechanism of action, suggest that the drug may cause harm to fetus when given to a pregnant woman.

Treatment given twice daily to female mice before mating and during the first week of pregnancy increased the amount of post-implantation loss at all tested doses (equal to or greater than 15 mg/kg/dose, or roughly 10 times the systemic exposure (AUC) in patients receiving the recommended initial dose).

Drugs can harm a fetus if they are given to a pregnant woman, according to research on animals. Pregnant women should get tested before beginning any treatment.

Females: If therapy is given to a pregnant woman, it may harm the fetus; therefore, during treatment and for one week following the last dosage, women who are capable of becoming pregnant should take appropriate contraception.

Males: Advise male partners who are capable of having children to use effective contraception during treatment and for one week following the last dose, based on results from studies conducted on animals.

Treatment may reduce fertility in both males and females who are capable of bearing children, according to research on animals.

Breastfeeding mothers are advised not to breastfeed during treatment and for two weeks following the final dose due to the possibility of severe adverse reactions in their children. There is no information available regarding the drug's presence in human milk, its effects on breastfed children, or its effects on milk production.

As per FDA, the safety and effectiveness of Axitinib (<18 years) in pediatric patients have not been established.

No specific renal impairment trial has been conducted.

According to population pharmacokinetic analyses, patients with pre-existing mild-to-severe renal impairment did not show a significant difference in clearance.

Mild (Child-Pugh A): Changing the starting dosage is unnecessary.

Moderate (Child-Pugh B): Reduce the first dose by about 50%; you can adjust the doses according to individual tolerance and safety.

Severe (Child-Pugh Class C): not investigated.

The physician should be vigilant about the knowledge pertaining to identifying and treating overdosage of Dasatinib.

Overconsumption of Axitinib could lead to dizziness, HTN, seizures, myelosuppression, and haemoptysis.

In cases of Axitinib overdose, there is no specific antidote. Management involves supportive care and monitoring vital signs, blood counts, and liver function. Activated charcoal may be administered to limit further absorption. Symptomatic interventions for neurotoxic effects or hematopoietic growth factors may be considered. Supportive care such as blood transfusions, antimicrobial therapy, and treatment for gastrointestinal issues may be necessary. Routine haematological evaluation should be conducted to prevent profound myelosuppression. Transfusions of blood or platelets should be given at any sign of bleeding.

A randomized, single-blind, two-way crossover trial involving 35 healthy participants assessed the impact of a single oral dose of INLYTA (5 mg) on the QTc interval in the presence and absence of 400 mg ketoconazole. For three hours after the dose, no appreciable differences in the mean QTc interval (i.e., >20 ms) were found between the two groups. However, increases smaller than 10 ms in the mean QTc interval cannot be completely ruled out.