Cabozantinib

Introduction Overview

Generic Name

cabozantinib

Brand Name

Cabometyx

Dosage Form

oral tablet (20 mg, 40 mg, 60 mg)

Drug Class

Multikinase inhibitors; VEGF/VEGFR inhibitors

Pharmacokinetics

Absorption:
Cabometyx (cabozantinib) is administered orally and is absorbed through the gastrointestinal tract. The bioavailability of cabozantinib tablets is influenced by food intake; hence, Cabometyx must be taken on an empty stomach—at least 1 hour before or 2 hours after eating—to assure consistent systemic absorption. The maximum plasma concentration (Cmax) of cabozantinib is typically reached within 2 to 5 hours post-dose. Studies have demonstrated that a high-fat meal can increase cabozantinib exposure, potentially increasing adverse effects, which necessitates careful administration timing.

Distribution:
Cabozantinib exhibits extensive tissue distribution with a high volume of distribution (Vd). It is highly bound to plasma proteins (~99.7%), primarily albumin, which affects its free pharmacologically active concentration. The drug can penetrate various tissues, including tumor microenvironments, to exert its antineoplastic actions. Protein binding and distribution may be influenced by pathological conditions such as hypoalbuminemia, commonly observed in patients with advanced cancer.

Metabolism:
Cabozantinib is primarily metabolized in the liver via cytochrome P450 enzyme CYP3A4. The metabolic process transforms cabozantinib into several metabolites, some of which possess pharmacologic activity. The metabolism is subject to modulation by concomitant administration of CYP3A4 inhibitors or inducers, which can respectively increase or decrease cabozantinib plasma concentrations, necessitating dose adjustments or close monitoring. Hepatic impairment can alter metabolism, leading to increased systemic exposure.

Elimination:
The drug and its metabolites are eliminated primarily through biliary excretion into feces, with renal excretion playing a minor role. The terminal half-life of cabozantinib is approximately 99 hours, supporting once-daily dosing. Steady-state plasma concentrations are generally achieved within 15 days of daily dosing. Hepatic impairment, as well as drug-drug interactions affecting CYP3A4 activity, can significantly impact elimination kinetics. The prolonged half-life requires careful consideration when planning surgery or managing adverse effects to allow adequate washout.

Dosage Forms

Available Dosage Forms:
Cabometyx is available exclusively as oral tablets in three dosage strengths: 20 mg, 40 mg, and 60 mg. These film-coated tablets are designed for oral administration and should be swallowed whole without crushing, chewing, or breaking, to maintain drug stability and absorption characteristics.

Dosages for Adults and Adolescents:
- Renal Cell Carcinoma (RCC):
- As a single agent: 60 mg orally once daily until disease progression or unacceptable toxicity.
- In combination with nivolumab: 40 mg orally once daily until disease progression or unacceptable toxicity.
- Hepatocellular Carcinoma (HCC):
- 60 mg orally once daily until disease progression or unacceptable toxicity.
- Differentiated Thyroid Cancer (DTC) and Neuroendocrine Tumors (pNET and epNET):
- Patients aged 12 years and older with bodyweight ≥40 kg: 60 mg once daily.
- Patients aged 12 years and older with bodyweight <40 kg: 40 mg once daily.
- Pediatric use is defined for patients 12 years and older in selected indications.

Specific Patient Populations:
- Patients with hepatic impairment require careful monitoring due to altered metabolism and possible increased exposure.
- Dosage adjustments may be necessary in cases of drug-drug interactions, particularly with CYP3A4 inhibitors or inducers.
- Patients undergoing surgery or dental procedures should discontinue Cabometyx at least 3 weeks before and delay restarting for 2 weeks post-procedure to reduce the risk of wound healing complications.
- Special consideration should be given to pregnant or breastfeeding patients due to teratogenicity and drug excretion factors.

Clinical Guidelines:
Cabometyx should be taken on an empty stomach with a full glass of water, avoiding grapefruit products and St. John's wort due to significant interaction potential. Adherence to prescribed dosing regimens and ongoing monitoring for toxicity is crucial for treatment efficacy and safety.

Mechanism Of Action

Cabometyx (cabozantinib) functions as a multitargeted tyrosine kinase inhibitor that interferes with multiple signaling pathways critical for tumor growth, angiogenesis, metastasis, and the maintenance of the tumor microenvironment. Its principal molecular targets include receptor tyrosine kinases such as VEGFR1, VEGFR2, VEGFR3, MET, AXL, and RET. By inhibiting these receptors, cabozantinib disrupts signaling pathways that are essential for angiogenesis—the generation of new blood vessels that supply tumors—and cellular proliferation.

At the cellular level, cabozantinib binds to the ATP-binding site of tyrosine kinase receptors, preventing phosphorylation and subsequent activation of downstream signaling cascades, including the PI3K/AKT and MAPK pathways. These pathways regulate key cellular functions, including survival, proliferation, migration, and invasion. Inhibition of MET and AXL also impairs tumor cell motility and invasion, curtailing metastatic spread.

Biochemically, cabozantinib’s simultaneous inhibition of multiple kinases exerts a synergistic effect by reducing tumor vascularization, promoting tumor cell apoptosis, and altering the tumor microenvironment to be less conducive for cancer progression. This broad kinase inhibitory profile differentiates Cabometyx from agents targeting a single receptor, offering a therapeutic advantage in tumors with complex pathogenesis involving multiple pathways.

Clinically, cabozantinib has demonstrated efficacy in delaying tumor progression in cancers traditionally resistant to monotherapies, such as advanced renal cell carcinoma and hepatocellular carcinoma. Comparative studies with similar drugs, such as sunitinib and sorafenib, indicate that cabozantinib’s multitargeted profile may provide improved progression-free survival and disease control by targeting additional pathways, including MET and AXL, associated with resistance mechanisms. Extensive clinical trials have confirmed these findings, supporting Cabometyx as a valuable targeted therapy option in oncology.

Pharmacological Actions

Inhibits multiple receptor tyrosine kinases including VEGFR1-3, MET, AXL, RET, which regulate angiogenesis and tumor growth.
Suppresses tumor angiogenesis by blocking VEGF-mediated endothelial cell proliferation and migration.
Reduces tumor cell proliferation and survival by interrupting intracellular signaling pathways such as PI3K/AKT and MAPK.
Blocks MET and AXL pathways that are critical for tumor cell motility, invasion, and metastasis.
Modifies the tumor microenvironment to inhibit support for cancer progression and resistance mechanisms.
Demonstrates anti-angiogenic and anti-metastatic effects contributing to delayed tumor progression.
Exhibits immunomodulatory effects when combined with immunotherapies such as nivolumab.
Targets pathways associated with resistance to other VEGFR inhibitors, providing efficacy in refractory cancers.
Displays durable disease control in advanced renal cell carcinoma, hepatocellular carcinoma, differentiated thyroid cancer, and certain neuroendocrine tumors.
Facilitates disruption of endothelial-pericyte interactions impacting tumor vasculature stability.

Therapeutic Or Clinical Uses

Treatment of advanced renal cell carcinoma (RCC), both as monotherapy and in combination with nivolumab.
Management of hepatocellular carcinoma (HCC) in patients previously treated with sorafenib.
Therapy of differentiated thyroid cancer (DTC) that is refractory to radioactive iodine treatment and has progressed after prior VEGFR-targeted therapy.
Treatment of pancreatic and extra-pancreatic neuroendocrine tumors (pNET and epNET) exhibiting progression on prior therapies.
Indicated for use in adolescent patients aged 12 years and older with specific tumor types under certain weight criteria.
Utilized as a targeted therapy option for patients with advanced malignancies expressing VEGF, MET, or AXL pathway activation.
Serves as second-line or later treatment in patients intolerant or resistant to multi-kinase inhibitor therapies.
Used to delay disease progression and extend survival in appropriate cancer patient populations.
Employed to manage tumors with complex oncogenic signaling relying on angiogenesis and kinases beyond VEGFR alone.
Combined with immune checkpoint inhibitors to enhance antitumor efficacy in select clinical settings.

Side Or Adverse Effects

Gastrointestinal effects including diarrhea, nausea, vomiting, constipation, and abdominal pain.
Fatigue and asthenia often manifesting as tiredness or decreased energy levels.
Hypertension due to VEGFR inhibition leading to vascular effects.
Hand-foot syndrome characterized by redness, pain, swelling, or rash on the palms and soles.
Oral mucositis or stomatitis with soreness, redness, and ulcerations in the mouth or throat.
Decreased appetite and weight loss impacting patient nutritional status.
Hepatotoxicity indicated by abnormal liver function tests and clinical jaundice.
Hematologic abnormalities including low white blood cell counts causing increased infection risk.
Bleeding complications ranging from mild (nosebleeds) to severe (gastrointestinal bleeding, hematuria).
Thromboembolic events including risk of blood clots and stroke symptoms.
Perforations or fistulas particularly affecting the gastrointestinal tract.
Hypocalcemia causing muscle spasms, numbness, or tingling sensations.
Changes in hair color and hair thinning or alopecia.
Dermatological reactions including rash and dry skin.
Rare severe hypersensitivity reactions such as anaphylaxis requiring emergency care.

Precautions

Perform comprehensive blood pressure monitoring due to risk of hypertension.
Assess liver function periodically; dose adjustments may be required in hepatic impairment.
Monitor for signs of hemorrhage or gastrointestinal perforation, especially in patients with prior risk factors.
Check for hypocalcemia symptoms and electrolytes regularly.
Avoid use in pregnant women due to teratogenicity; effective contraception is mandatory during and 4 months post-treatment.
Discontinue prior to surgery or invasive dental procedures 3 weeks beforehand and delay resumption for 2 weeks post-procedure.
Caution in patients with pre-existing bleeding disorders or active wounds as drug may impair healing.
Avoid grapefruit and St. John's wort products that affect cabozantinib metabolism.
Regularly evaluate thyroid function and adrenal glands as abnormalities may develop.
Use caution when combined with immunotherapy agents; monitor for enhanced immune-related adverse effects.
Dose reduction or interruption may be necessary in cases of severe toxicity or adverse reactions.
Educate patients regarding the importance of adherence to administration schedule and monitoring visits.
Consider potential interactions with other CYP3A4 metabolized medications when initiating or stopping therapy.
Advise patients to report any new neurological symptoms immediately due to risk of stroke or blood clots.
Avoid breastfeeding during treatment and for at least 4 months after discontinuation.

Warnings

Risk of gastrointestinal perforation or fistula formation; immediate medical evaluation required if severe abdominal pain or swallowing difficulty occurs.
Potential for serious and sometimes fatal bleeding events including gastrointestinal and intracranial hemorrhages.
Hypertension may occur or worsen and requires prompt management to prevent cardiovascular complications.
Serious wound healing complications; discontinue treatment prior to elective surgeries.
Hypocalcemia has been reported and may present with neuromuscular symptoms.
Increased risk of thromboembolic events such as stroke, myocardial infarction, and deep vein thrombosis.
Use in pregnancy is contraindicated due to embryo-fetal toxicity and teratogenic effects.
Possible severe skin reactions including hand-foot syndrome and rash requiring treatment interruption or discontinuation.
Potential for hepatotoxicity with monitoring of liver enzymes essential during treatment.
Cabozantinib may lower white blood cell counts, increasing infection susceptibility.
Monitoring for adrenal insufficiency symptoms is advised.
Avoid switching between different cabozantinib formulations as dosage and bioavailability differ.
Concomitant use with strong CYP3A4 inhibitors or inducers can lead to life-threatening adverse effects or sub-therapeutic efficacy.
Patients should be informed about signs of stroke, bleeding, and thrombotic events for early detection.
Risk of severe allergic reactions warrants immediate discontinuation and emergency care if symptoms occur.

Contraindication

Known hypersensitivity to cabozantinib or any component of Cabometyx formulation.
Pregnancy due to significant risk of fetal harm and teratogenicity.
Patients with active gastrointestinal perforation or fistula.
Concurrent use with cabozantinib capsules (Cometriq), as formulations are not interchangeable.
Uncontrolled hypertension or significant bleeding disorders that contraindicate angiogenesis inhibitors.
Severe hepatic impairment without appropriate dose adjustments and monitoring.
Use in breastfeeding women due to unknown harmful effects on infant.
Patients unable to comply with required monitoring and preventive measures for side effects.
Patients with recent history of significant cardiovascular events without stabilization.
Known severe hypersensitivity reactions to other multitargeted kinase inhibitors.

Drug Interactions

Strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin) can increase cabozantinib plasma levels, raising toxicity risk; dose adjustment may be necessary.
Strong CYP3A4 inducers (e.g., rifampin, St. John's wort) can decrease cabozantinib concentrations, reducing efficacy.
Grapefruit and grapefruit juice inhibit metabolism leading to elevated cabozantinib levels; concomitant use should be avoided.
Concurrent anticoagulants or antiplatelet agents may enhance bleeding risk when combined with cabozantinib.
Use with immunotherapy agents such as nivolumab may increase immune-related adverse effects.
Drugs that prolong QT interval may compound arrhythmia risks with cabozantinib.
Co-administration with other anti-hypertensive agents requires close monitoring due to exacerbation of hypertension.
Substances that affect liver enzyme function, including some herbal supplements and over-the-counter medications, may alter cabozantinib pharmacokinetics.
CYP3A4 substrates with narrow therapeutic windows may have altered levels due to cabozantinib’s enzyme interaction potential.
Inhibitors of P-glycoprotein transporters may affect cabozantinib distribution and elimination.
Concurrent use with strong CYP2C8 inhibitors may also influence cabozantinib metabolism.
Combination with drugs causing impaired wound healing increases the risk of complications.
Concomitant use of live vaccines is generally not recommended due to immunosuppressive effects.
Medications affecting electrolyte balance should be used cautiously to avoid compounding side effects.
Patients should inform healthcare providers about all medications, supplements, and herbal products to avoid interactions.

Preparations Of The Drug

Cabometyx oral tablets are film-coated and supplied in 20 mg, 40 mg, and 60 mg strengths.
Tablets are provided in blister packs or bottles depending on the manufacturer and prescription requirements.
Packaging includes child-resistant features to prevent accidental ingestion.
Tablets are designed for oral use, to be swallowed whole and not to be crushed, chewed, or split.
Storage conditions recommend keeping the tablets at room temperature, away from moisture and heat.
Dosing is prescribed in tablet counts according to mg strength to match individualized daily dose.
Patient information leaflets accompany the tablets to instruct on administration and precautions.
Available only as branded Cabometyx tablets; generic versions are not currently available.
Manufactured by Exelixis, Inc. and distributed in accordance with FDA-approved labeling.
Not interchangeable with cabozantinib capsules marketed as Cometriq, which have different dosing and indications.
Supplied with medication guides emphasizing safety warnings and side effect management.
Prescribing healthcare providers must ensure correct formulation and dosing to avoid medication errors.
Tablets should be packaged and dispensed in original container until use to protect from environmental exposure.
Handling instructions include avoiding exposure to children and not sharing medication with others.
Pharmacy dispensing should include counseling regarding administration without food and avoidance of contraindicated substances.