Usage
Capmatinib is prescribed for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have a mutation that leads to mesenchymal-epithelial transition (MET) exon 14 skipping. This mutation is detected by an FDA-approved test. It’s important to note that this indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval might depend on verification and description of clinical benefit in confirmatory trials.
Capmatinib’s pharmacological classification is a kinase inhibitor, specifically a type Ib MET tyrosine kinase inhibitor.
It works by selectively inhibiting the MET receptor tyrosine kinase, thereby blocking the signaling pathways that promote tumor growth and proliferation in cancers with MET exon 14 skipping alterations.
Alternate Names
Capmatinib is also known by its international nonproprietary name (INN) capmatinib. A popular brand name under which it’s marketed is Tabrecta.
How It Works
Pharmacodynamics: Capmatinib selectively targets the MET receptor tyrosine kinase. By inhibiting this kinase, the drug disrupts downstream signaling cascades crucial for tumor cell growth, survival, and proliferation, specifically in NSCLC with MET exon 14 skipping alterations. This leads to a reduction in tumor growth and progression.
Pharmacokinetics:
- Absorption: Capmatinib is rapidly absorbed after oral administration, reaching peak plasma concentrations (Cmax) in approximately 1 to 2 hours under fasting conditions and 4-6 hours under fed conditions. Its absorption is estimated to be greater than 70%, and food does not significantly alter its bioavailability.
- Distribution: Capmatinib exhibits high plasma protein binding (96%) and has an apparent mean volume of distribution at steady-state of 164 L.
- Metabolism: Capmatinib is primarily metabolized in the liver via CYP3A4, although it also inhibits CYP1A2 and may increase the exposure of some other substrates.
- Elimination: Capmatinib is eliminated with an effective half-life of 6.5 hours.
Mode of Action: Capmatinib competitively binds to the ATP-binding site of the MET receptor tyrosine kinase, inhibiting its catalytic activity. This prevents autophosphorylation of the receptor and activation of downstream signaling pathways involved in cell growth and proliferation. Capmatinib is classified as a type Ib inhibitor, meaning that it binds specifically to the inactive conformation of the MET kinase. It’s selective for MET, showing limited activity against other kinases.
Receptor binding, enzyme inhibition, or neurotransmitter modulation: Capmatinib binds to the MET receptor tyrosine kinase, inhibiting its activity. It also inhibits CYP1A2, P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), MATE1, and MATE2K, which can lead to drug interactions. It does not modulate neurotransmitters.
Elimination pathways: Capmatinib is predominantly eliminated through hepatic metabolism primarily by CYP3A4 with minor involvement from CYP2C9.
Dosage
Standard Dosage
Adults:
The recommended dose of Capmatinib for adults is 400 mg orally twice daily with or without food. Treatment duration depends on individual safety, tolerability, and clinical benefit.
Children:
The safety and effectiveness of Capmatinib in pediatric patients have not been established.
Special Cases:
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Elderly Patients: No dose adjustment is required for patients 65 years or older.
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Patients with Renal Impairment: No dose adjustment is recommended for patients with mild or moderate renal impairment. Caution should be exercised in patients with severe renal impairment, as Capmatinib has not been studied in this population.
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Patients with Hepatic Dysfunction: No dose adjustment is necessary for patients with mild, moderate, or severe hepatic impairment.
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Patients with Comorbid Conditions: Use with caution in patients with lung or breathing problems (e.g., interstitial lung disease, pneumonitis), as it may worsen these conditions. Close monitoring is required for patients with pre-existing liver disease.
Clinical Use Cases
Capmatinib’s clinical use is specifically focused on metastatic NSCLC with confirmed MET exon 14 skipping mutations. Its use in other settings, like intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations, is not established and not currently recommended.
Dosage Adjustments
Dose reductions may be necessary based on individual safety and tolerability. Dosage modifications may be required for the management of specific adverse reactions.
Side Effects
Common Side Effects:
Swelling of extremities (peripheral edema), nausea, fatigue, vomiting, shortness of breath (dyspnea), decreased appetite, non-cardiac chest pain, back pain, fever (pyrexia), weight loss, constipation, diarrhea, and cough.
Rare but Serious Side Effects:
Interstitial lung disease/pneumonitis, hepatotoxicity, pancreatic toxicity, hypersensitivity reactions. Severe eye symptoms (sudden vision loss, blurred vision, etc.), serious heart symptoms (fast, irregular heartbeat, etc.), severe headache, confusion, slurred speech, arm or leg weakness.
Long-Term Effects:
Potential long-term effects from prolonged Capmatinib use are not fully characterized but may include chronic complications related to the common and serious side effects described above.
Adverse Drug Reactions (ADR):
Clinically significant ADRs include ILD/pneumonitis, hepatotoxicity, and pancreatic toxicity. Hypersensitivity reactions requiring immediate intervention may also occur.
Contraindications
Hypersensitivity to capmatinib or any of its components is a contraindication.
Drug Interactions
Capmatinib is a substrate of CYP3A4 and an inhibitor of CYP1A2, P-gp, BCRP, MATE1, and MATE2K. Clinically significant interactions can occur with:
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Strong CYP3A4 Inhibitors: Concomitant use can increase capmatinib exposure and increase the risk of adverse effects. Close monitoring is necessary.
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Strong and Moderate CYP3A4 Inducers: Concomitant use should be avoided, as these agents can decrease capmatinib exposure and reduce its efficacy.
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CYP1A2 substrates: Concomitant use can increase the exposure of the substrate (e.g., theophylline, tizanidine). Dose reductions of the co-administered medications may be required.
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P-gp and BCRP Substrates: Co-administration can increase the substrate’s exposure, necessitating dose adjustments. Examples include digoxin, rosuvastatin, and methotrexate.
Other drugs like apalutamide, bosentan, carbamazepine, and conivaptan can also interact with capmatinib by affecting CYP3A4 metabolism and altering its effect.
Interactions may also occur with over-the-counter drugs, supplements, and food items like grapefruit, Seville oranges, and star fruit. Caffeine’s effects can be increased and prolonged with Capmatinib, so monitoring caffeine intake is essential.
Pregnancy and Breastfeeding
Capmatinib is contraindicated during pregnancy due to potential fetal harm based on animal studies and its mechanism of action. It should not be used during breastfeeding due to the potential for serious adverse reactions in breastfed infants. Effective contraception is crucial for both females and males during treatment and for at least 7 days after the last dose.
Drug Profile Summary
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Mechanism of Action: Selective inhibitor of MET tyrosine kinase, primarily in NSCLC with MET exon 14 skipping mutations.
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Side Effects: Peripheral edema, nausea, vomiting, fatigue, dyspnea, decreased appetite, cough, ILD/pneumonitis, hepatotoxicity, pancreatic toxicity.
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Contraindications: Hypersensitivity to Capmatinib, pregnancy.
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Drug Interactions: Strong CYP3A4 inhibitors and inducers, CYP1A2 substrates, P-gp and BCRP substrates.
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Pregnancy & Breastfeeding: Contraindicated in pregnancy and during breastfeeding.
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Dosage: 400 mg orally twice daily for adults.
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Monitoring Parameters: Liver function tests (ALT, AST, bilirubin), amylase, lipase, pulmonary function tests, signs and symptoms of hypersensitivity.
Popular Combinations
Capmatinib is typically used as a monotherapy. Combinations with other anticancer agents are not yet established.
Precautions
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General Precautions: Pre-screening for allergies, liver and renal function, and pulmonary function is recommended.
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Specific Populations: Avoid in pregnancy and breastfeeding. Caution advised in patients with severe renal impairment and pre-existing lung or breathing problems. No specific precautions for elderly or menstruating individuals are required, other than standard monitoring.
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Lifestyle Considerations: Patients should avoid excessive sun exposure and use appropriate sun protection. Alcohol and smoking may exacerbate some side effects and should be limited. No specific dietary restrictions are required, but grapefruit and related fruits should be avoided.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Capmatinib?
A: The recommended dosage for adults is 400 mg orally twice daily, with or without food.
Q2: What is the mechanism of action of Capmatinib?
A: Capmatinib is a selective inhibitor of the MET receptor tyrosine kinase, blocking signaling pathways involved in tumor growth.
Q3: What are the common side effects of Capmatinib?
A: Common side effects include peripheral edema, nausea, fatigue, vomiting, dyspnea, decreased appetite, and cough.
Q4: What are the serious side effects of Capmatinib?
A: Serious side effects include ILD/pneumonitis, hepatotoxicity, pancreatic toxicity, and hypersensitivity reactions.
Q5: What are the contraindications for Capmatinib?
A: Contraindications include hypersensitivity to Capmatinib and pregnancy.
Q6: Can Capmatinib be used during pregnancy or breastfeeding?
A: No, Capmatinib is contraindicated during pregnancy and breastfeeding.
Q7: What are the key drug interactions with Capmatinib?
A: Key drug interactions involve strong CYP3A4 inhibitors and inducers, CYP1A2 substrates, and P-gp/BCRP substrates.
Q8: How should Capmatinib be administered?
A: Capmatinib is administered orally as tablets, twice daily, with or without food. Tablets should be swallowed whole.
Q9: What should patients be monitored for during Capmatinib treatment?
A: Patients should be monitored for liver function (ALT, AST, bilirubin), pancreatic enzymes (amylase and lipase), pulmonary function, and any signs of hypersensitivity.
Q10: Is dose adjustment needed for elderly patients?
A: No, dose adjustment is not typically needed for elderly patients.
