What is Capmatinib Hydrochloride used for?

Capmatinib hydrochloride, known by the trade name Tabrecta, is a promising pharmaceutical agent primarily targeting non-small cell lung cancer (NSCLC) with specific genetic aberrations. Developed by Novartis, this drug is a selective MET inhibitor. The MET gene encodes for a protein called hepatocyte growth factor receptor (HGFR), which is involved in pathways that regulate cell growth, survival, and migration. When mutated, the MET gene can play a significant role in oncogenesis, particularly in non-small cell lung cancer.

Capmatinib hydrochloride is particularly targeted towards patients exhibiting MET exon 14 skipping mutations. These mutations, present in approximately 3-4% of NSCLC cases, can drive cancer progression by causing aberrant activation of the MET pathway. The drug's approval by the U.S. Food and Drug Administration (FDA) in May 2020 for the treatment of adult patients with metastatic NSCLC harboring MET exon 14 skipping mutations marked a significant milestone. Ongoing research and clinical trials continue to investigate the potential of capmatinib hydrochloride in treating other cancers characterized by MET dysregulation, further expanding its therapeutic scope.

Capmatinib Hydrochloride Mechanism of Action

Capmatinib hydrochloride functions by selectively inhibiting the MET receptor tyrosine kinase. The MET receptor is activated by its ligand, hepatocyte growth factor (HGF), which triggers a cascade of downstream signaling pathways, including the RAS-ERK, PI3K-AKT, and STAT3 pathways. These pathways are vital for cell proliferation, survival, and motility. In normal cells, this signaling is tightly regulated, but in cancer cells with MET exon 14 skipping mutations, the receptor is constitutively activated, leading to uncontrolled cellular proliferation and metastasis.

Capmatinib hydrochloride binds to the ATP-binding site of the MET receptor, preventing its phosphorylation and subsequent activation of downstream signaling. This inhibition leads to reduced tumor cell proliferation, increased apoptosis (programmed cell death), and inhibition of metastasis. The selectivity of capmatinib for the MET receptor allows for targeted therapy, which minimizes damage to normal, healthy cells and reduces the severity of side effects typically associated with conventional chemotherapies.

How to Use Capmatinib Hydrochloride

Capmatinib hydrochloride is administered orally, with patients typically taking two tablets twice daily. The recommended dosage is 400 mg per tablet, leading to a total daily dose of 800 mg. It is advised to take the medication with or without food, but consistency in the timing of doses is crucial to maintain steady plasma concentrations of the drug. Patients should swallow the tablets whole and avoid crushing, chewing, or splitting them.

Upon administration, capmatinib hydrochloride is absorbed through the gastrointestinal tract, with peak plasma concentrations typically reached within 1-2 hours. The drug exhibits a half-life of approximately 6-8 hours, necessitating twice-daily dosing to maintain its therapeutic effect. The onset of action can vary among individuals, but many patients may begin to experience clinical benefits within the first few weeks of treatment.

Regular monitoring through imaging studies, such as CT scans or MRIs, and biomarker assessments, such as MET exon 14 mutation status, are critical during treatment to evaluate the drug's efficacy and adjust dosing if necessary. Physicians may also conduct routine blood tests to monitor for potential adverse effects and ensure the patient's safety throughout the treatment period.

What is Capmatinib Hydrochloride Side Effects

Like all medications, capmatinib hydrochloride is associated with a range of potential side effects. Common adverse reactions include nausea, vomiting, fatigue, peripheral edema, and decreased appetite. These side effects are generally manageable and can often be mitigated with supportive care measures such as antiemetics for nausea or dietary modifications for appetite loss.

However, some patients may experience more severe side effects, necessitating close monitoring and, in some cases, discontinuation of the drug. Serious adverse reactions include interstitial lung disease (ILD) or pneumonitis, hepatotoxicity, and photosensitivity. Interstitial lung disease is a rare but potentially life-threatening condition that can manifest as new or worsening respiratory symptoms such as cough, dyspnea, or fever. Patients presenting with these symptoms should undergo prompt evaluation, and if ILD is confirmed, capmatinib must be permanently discontinued.

Hepatotoxicity, indicated by elevated liver enzymes (AST, ALT, or bilirubin levels), is another significant concern. Regular liver function tests are crucial, and dose adjustments or discontinuation may be necessary in cases of severe liver enzyme elevation. Additionally, patients are advised to avoid excessive sun exposure and use sun protection measures, as capmatinib can increase skin sensitivity to sunlight, leading to severe sunburns or skin reactions.

Capmatinib hydrochloride is contraindicated in patients with known hypersensitivity to the drug or any of its excipients. The drug's safety and efficacy in pediatric populations have not been established, and it should be used cautiously in patients with preexisting liver disease, as they may be at a higher risk for hepatotoxicity.

What Other Drugs Will Affect Capmatinib Hydrochloride

The pharmacokinetics of capmatinib hydrochloride can be influenced by concomitant medications that affect its absorption, metabolism, or excretion. Capmatinib is primarily metabolized by the cytochrome P450 enzyme CYP3A4. Therefore, drugs that induce or inhibit CYP3A4 can significantly alter capmatinib plasma levels.

CYP3A4 inhibitors, such as ketoconazole, itraconazole, ritonavir, and grapefruit juice, can increase capmatinib plasma concentrations, potentially intensifying its therapeutic and adverse effects. Conversely, CYP3A4 inducers, like rifampin, carbamazepine, phenytoin, and St. John's Wort, can decrease capmatinib levels, potentially reducing its efficacy. Patients should inform their healthcare providers about all medications they are taking, including over-the-counter drugs and dietary supplements, to avoid potential drug interactions.

Additionally, capmatinib hydrochloride can affect the pharmacokinetics of other drugs metabolized by the same enzyme. Caution is warranted when co-administering capmatinib with other CYP3A4 substrates, as it may alter their plasma concentrations and therapeutic effects. Physicians should closely monitor patients for any signs of altered drug efficacy or toxicity and adjust dosages as needed.

In summary, capmatinib hydrochloride represents a significant advancement in the targeted therapy of MET-altered non-small cell lung cancer. Its selective inhibition of the MET receptor offers a tailored approach to treatment, minimizing damage to healthy cells and improving patient outcomes. However, careful monitoring for side effects and potential drug interactions is critical to ensuring the safety and efficacy of this innovative therapy.