Usage
Cabozantinib is prescribed for the treatment of advanced renal cell carcinoma (RCC), hepatocellular carcinoma (HCC), and medullary thyroid cancer (MTC). It is classified as a kinase inhibitor, specifically a multikinase inhibitor, targeting receptor tyrosine kinases (RTKs), including VEGFR1, VEGFR2, VEGFR3, MET, AXL, RET, KIT, and TIE2. The mechanism of action involves inhibiting these RTKs, which play a crucial role in tumor growth, angiogenesis (blood vessel formation), and metastasis.
Alternate Names
Cabozantinib is marketed under the brand names Cabometyx (tablets) and Cometriq (capsules).
How It Works
Pharmacodynamics: Cabozantinib exerts its anti-cancer effects by inhibiting multiple RTKs involved in tumor growth and progression. This inhibition leads to a decrease in tumor cell proliferation, angiogenesis, and metastatic potential.
Pharmacokinetics:
- Absorption: Cabozantinib is absorbed orally, with food increasing its absorption. It’s recommended to take the medication at least one hour before or two hours after a meal.
- Metabolism: Primarily metabolized in the liver by CYP3A4, with minor contributions from CYP1A2 and CYP2C9.
- Elimination: Excreted primarily via feces, with a small portion eliminated in urine. The half-life ranges from 55 to 99 hours, allowing for once-daily dosing.
Mode of Action: Cabozantinib binds to the ATP-binding pockets of target RTKs, preventing phosphorylation and activation, thereby disrupting downstream signaling pathways essential for tumor growth and spread.
Receptor Binding/Enzyme Inhibition: Cabozantinib acts as a competitive inhibitor of the target RTKs.
Elimination Pathways: Predominantly hepatic metabolism via CYP3A4, with fecal excretion as the primary route of elimination.
Dosage
Standard Dosage
Adults:
- RCC (Cabometyx): 60 mg orally once daily. For combination therapy with nivolumab, 40 mg orally once daily.
- HCC (Cabometyx): 60 mg orally once daily.
- MTC (Cometriq): 140 mg orally once daily (as capsules).
- DTC (Cabometyx): 60 mg orally once daily for BSA ≥ 1.2 m2. 40 mg orally once daily for BSA < 1.2 m2.
Children:
- DTC (Cabometyx): For patients 12 years and older, dosing is based on BSA as mentioned above. Use in children younger than 12 years has not been established. For other indications, use and dose must be determined by the doctor.
Special Cases:
- Elderly Patients: No specific dose adjustment is recommended, but caution is advised due to potential age-related decline in organ function.
- Patients with Renal Impairment: Use with caution in mild or moderate renal impairment. Not recommended in severe renal impairment.
- Patients with Hepatic Dysfunction: No dose adjustment is needed for mild impairment. For moderate impairment (Child-Pugh B), reduce the dose to 40 mg once daily. Avoid use in severe impairment (Child-Pugh C).
- Patients with Comorbid Conditions: Exercise caution in patients with hypertension, cardiac conditions, history of bleeding, or GI issues.
Clinical Use Cases
Cabozantinib is not typically used in the context of intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations like status epilepticus or cardiac arrest. Its primary use is in the targeted therapy of specific cancers as outlined above.
Dosage Adjustments
Dosage adjustments may be required due to adverse events or drug interactions. Common dose reductions are to 40 mg daily and then to 20 mg daily or 20 mg every other day, depending on tolerability.
Side Effects
Common Side Effects:
Diarrhea, fatigue, palmar-plantar erythrodysesthesia (PPE), decreased appetite, hypertension, nausea, vomiting, weight loss, constipation.
Rare but Serious Side Effects:
Hemorrhage, GI perforations, fistulas, thrombotic events, hypertensive crisis, hepatotoxicity, adrenal insufficiency, proteinuria, osteonecrosis of the jaw, impaired wound healing, reversible posterior leukoencephalopathy syndrome (RPLS), hypocalcemia.
Long-Term Effects:
Potential long-term effects include chronic complications related to the above-mentioned rare but serious side effects. Reduced fertility has also been observed.
Adverse Drug Reactions (ADR):
Any of the rare but serious side effects mentioned above constitute clinically significant ADRs requiring immediate intervention.
Contraindications
No absolute contraindications. Relative contraindications include severe hepatic impairment, recent history of severe hemorrhage, and pregnancy.
Drug Interactions
- CYP3A4 Inhibitors: Co-administration with strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir, clarithromycin) can increase cabozantinib exposure. Dose adjustments may be necessary.
- CYP3A4 Inducers: Co-administration with strong CYP3A4 inducers (e.g., rifampicin, phenytoin, carbamazepine) can decrease cabozantinib exposure and potentially reduce efficacy.
- Other Interactions: Avoid concomitant use with St. John’s wort.
Pregnancy and Breastfeeding
- Pregnancy Safety Category: Pregnancy category D (Australia); not assigned (US FDA), based on evidence suggesting potential fetal harm. Cabozantinib can cause fetal harm and is contraindicated during pregnancy. Effective contraception is essential during and for at least 4 months after treatment.
- Breastfeeding: Cabozantinib may be excreted in breast milk. Breastfeeding is contraindicated during and for at least 4 months after treatment.
Drug Profile Summary
- Mechanism of Action: Multikinase inhibitor targeting RTKs involved in tumor growth and angiogenesis.
- Side Effects: Diarrhea, fatigue, PPE, hypertension, nausea, vomiting, weight loss, and serious risks like hemorrhage, GI perforation, and thrombotic events.
- Contraindications: Recent significant hemorrhage, pregnancy, severe hepatic impairment.
- Drug Interactions: CYP3A4 inhibitors and inducers, St. John’s Wort.
- Pregnancy & Breastfeeding: Contraindicated.
- Dosage: Varies depending on indication and patient factors. See detailed dosage section.
- Monitoring Parameters: Blood pressure, liver function tests, complete blood count, signs of bleeding or GI complications, calcium levels.
Popular Combinations
Cabozantinib is often used in combination with nivolumab for the first-line treatment of advanced RCC.
Precautions
- General Precautions: Assess for history of bleeding, GI conditions, cardiovascular disease, and hepatic/renal impairment. Monitor blood pressure, liver function, and complete blood count.
- Specific Populations: See “Special Cases” under “Dosage.” Contraindicated in pregnancy and breastfeeding. Monitor adolescents for growth plate abnormalities.
- Lifestyle Considerations: Advise patients to avoid grapefruit and its juice. Caution regarding driving and operating machinery due to potential fatigue and dizziness.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Cabozantinib?
A: The recommended dosage varies depending on the indication. For RCC and HCC, it is typically 60 mg orally once daily. For MTC, 140 mg orally once daily (capsules). For DTC, dosing depends on BSA (60 mg daily for BSA ≥ 1.2 m2 and 40 mg daily for BSA < 1.2 m2).
Q2: What are the most common side effects of Cabozantinib?
A: Diarrhea, fatigue, PPE, decreased appetite, hypertension, nausea, vomiting, weight loss, and constipation are the most frequently reported side effects.
Q3: What are the serious side effects to watch out for with Cabozantinib?
A: Serious side effects can include hemorrhage, GI perforations/fistulas, thrombotic events, hypertensive crisis, and hepatotoxicity.
Q4: Can Cabozantinib be used in patients with liver or kidney problems?
A: It can be used with caution in patients with mild to moderate renal or hepatic impairment. Dose adjustments may be needed for moderate hepatic impairment. Avoid use in severe hepatic or renal dysfunction.
Q5: What are the key drug interactions with Cabozantinib?
A: Significant interactions occur with strong CYP3A4 inhibitors and inducers. Concomitant use with St. John’s Wort should also be avoided.
Q6: Can Cabozantinib be used during pregnancy or breastfeeding?
A: No. Cabozantinib is contraindicated in pregnancy and breastfeeding due to the risk of fetal harm and potential excretion in breast milk.
Q7: What monitoring is required during Cabozantinib therapy?
A: Monitor blood pressure, liver function tests, complete blood count, and watch for signs of bleeding, GI complications, or electrolyte imbalances.
Q8: What should patients be counseled on regarding lifestyle while on Cabozantinib?
A: Patients should avoid grapefruit and its juice. Caution should be exercised when driving or operating machinery due to the potential for fatigue and dizziness. Effective contraception is crucial during and for 4 months after treatment.
Q9: What is the difference between Cabometyx and Cometriq?
A: Both are brand names for cabozantinib, but Cabometyx is formulated as tablets and is used for RCC, HCC, and DTC, while Cometriq is formulated as capsules and is specifically used for MTC. They are not interchangeable.
