Zykadia
MET exon 14 skipping
Generic Name
MET exon 14 skipping
Mechanism
- Capmatinib is a covalent, irreversible inhibitor of the c‑Met (MET) tyrosine kinase receptor.
- It binds covalently to the cysteine residue in the ATP‑binding pocket of the kinase domain, permanently disabling phosphorylation.
- By blocking the HGF‑c‑Met axis, capmatinib suppresses downstream signaling pathways that drive tumor proliferation, invasion, migration, and angiogenesis (PI3K/AKT, RAS/MAPK, STAT3).
- The inhibition is highly selective for mutant c‑Met (exon 14‑skipping), sparing wild‑type MET and reducing off‑target activity.
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Pharmacokinetics
| Parameter | Detail |
| Absorption | Rapid oral absorption; peak plasma concentration (Tmax) ~2 h post‑dose. |
| Bioavailability | ~30 %–40 % when taken with food; food does not significantly alter AUC. |
| Distribution | Extensive tissue penetration; volume of distribution ~2.8 L/kg. |
| Metabolism | Primarily hepatic via CYP3A4 and to a lesser extent CYP2D6. |
| Elimination | Metabolites excreted mainly in feces; remainder in urine. Clearance ~10 L/h. |
| Half‑life | ~24 h at steady state, supporting once‑daily dosing. |
| Drug–Drug Interactions | Strong CYP3A4 inhibitors (e.g., ketoconazole) ↑ exposure; strong inducers (e.g., rifampin) ↓ plasma levels. Avoid concomitant use of potent CYP3A4 modulators unless dose adjustment is planned. |
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Indications
- First‑line treatment of adults with metastatic or locally advanced NSCLC carrying a detected MET exon 14 skipping mutation (approved by FDA, EMA, and other regulatory agencies).
- Second‑line setting may be considered after progression on platinum‑based chemotherapy if no alternative targeted therapies are available.
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Contraindications
| Category | Details |
| Contraindications | Known hypersensitivity to capmatinib, its excipients, or any component of the formulation. |
| Warnings |
• Hepatotoxicity – monitor LFTs; discontinue if ALT/AST > 3 × ULN with symptoms. • Interstitial lung disease (ILD) – early signs (cough, dyspnea) warrant prompt evaluation. • Hypertension – baseline BP monitoring; treat per standard guidelines. • Pregnancy – Category X; contraindicated; counsel patients on effective contraception. • Concurrent use with strong CYP3A4 inhibitors/inducers – avoid or adjust dose. |
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Dosing
| Population | Dose | Frequency | Admin Notes |
| Adults (≥ 18 yr) | 200 mg | Once daily, oral | Take with a light meal to avoid GI upset; food does not markedly alter exposure. |
| Mild/Moderate hepatic impairment (Child‑Pugh A/B) | 200 mg | Once daily | No adjustment necessary. |
| Severe hepatic impairment (Child‑Pugh C) | 150 mg | Once daily | Reduce by 25 %. |
| Renal impairment | 200 mg | Once daily | No dose modification up to creatinine clearance ≥ 30 mL/min; caution below. |
*For patients who do not tolerate the standard dose, consider a dose reduction to 150 mg daily. Re‑titrate cautiously based on tolerance.*
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Adverse Effects
| Category | Examples (≥ 10 %) | Serious (≥ 1 % or higher) |
| Hepatic | ALT/AST ↑, jaundice | Severe hepatotoxicity (ALT > 3×ULN w/ symptoms), fulminant hepatic failure |
| Cardiovascular | Hypertension, tachycardia | Grade ≥ 3 hypertension, congestive heart failure (rare) |
| Pulmonary | Cough, mild dyspnea, interstitial lung disease | Interstitial pneumonitis, ILD requiring therapy discontinuation |
| Gastrointestinal | Nausea, vomiting, constipation | Severe diarrhea (≥ 5 × loose stools/24 h) |
| Dermatologic | Rash, pruritus | Severe rash (photo‑reactive, exfoliative) |
| Metabolic | Hypertriglyceridemia, hyperglycemia | Hypercholesterolemia, diabetes exacerbation |
| Other | Peripheral edema, fatigue, decreased appetite | Anemia, thrombocytopenia, neutropenia (rare) |
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Monitoring
- Baseline and periodic liver function tests (ALT, AST, bilirubin, ALP).
- Baseline and periodic complete blood count (CBC).
- Baseline and periodic renal function (serum creatinine, eGFR).
- Baseline and periodic blood pressure and heart rate.
- Baseline and periodic ECG (monitor QT interval if combined with QT‑prolonging drugs).
- Pulmonary monitoring – evaluate symptoms of cough or shortness of breath; consider imaging if ILD suspected.
- Drug–drug interaction assessment – review concomitant medications for CYP3A4 implications.
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Clinical Pearls
1. Irreversible binding: The covalent interaction means that resistance due to reversible mutational changes in the ATP‑binding pocket is less common compared with first‑generation MET inhibitors.
2. Interstitial lung disease: ILD can manifest early (within 2–4 weeks). High index of suspicion is necessary; discontinue capmatinib at the first sign of unexplained dyspnea or cough.
3. Hypertension management: Treat per the ACC/AHA hypertension guideline; consider calcium‑channel blockers or ACE inhibitors if needed.
4. Food effect: While absolute bioavailability is ~30 %, co‑administration with a high‑fat meal can increase Cmax modestly; for consistency, advise patients to take the dose at the same time daily.
5. CYP3A4 interactions: Strong inhibitors can raise exposure by > 2‑fold; patients on statins (e.g., simvastatin) should switch to a lower‑risk agent (e.g., rosuvastatin) to avoid hypercholesterolemia.
6. Resistance patterns: Secondary mutations in the Cys‑1150 region may confer resistance; in such cases, consider switching to a different class of MET inhibitor (sotorasib, crizotinib) or enrolling in trials.
7. First‑line status: Capmatinib’s efficacy (median PFS ~9 months) surpasses platinum chemotherapy in the MET exon 14‑skipping NSCLC cohort; thus, molecular testing is mandatory for all advanced NSCLC patients.
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