selumetinib
Selumetinib
Generic Name
Selumetinib
Mechanism
Selumetinib is an orally‑administered, selective inhibitor of the mitogen‑activated protein kinase (MEK) 1/2 pathway.
• Blocks phosphorylation of downstream ERK1/2, thereby interrupting signal transduction that drives cell proliferation, survival, and migration.
• Inhibits the MAPK/ERK pathway in tumors harboring activating RAS/MAPK alterations (e.g., neurofibromatosis type 1, BRAF V600E).
• Enhances antitumor immunity by decreasing regulatory T‑cell activity in certain tumor microenvironments.
*Key take‑away*: Selumetinib stops the “growth signal” of MEK, curbing cancer cell division.
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Pharmacokinetics
- Administration: Oral capsules, taken with food (high‑fat meal increases absorption ~2‑fold).
- Absorption: ~60–70 % bioavailability; peak plasma concentration (C_max) reached ≈1–3 h post‑dose.
- Distribution: Extensive (V_d ≈ 100 L); highly protein‑bound (~97 %).
- Metabolism: Primarily CYP3A4‑mediated; minor contributions from CYP2C19.
- Elimination: Excreted mainly via biliary/fecal routes; half‑life ≈13 h in healthy adults.
- Drug‑Drug Interactions: Strong CYP3A4 inhibitors (e.g., ketoconazole) ↑ selumetinib exposure; strong CYP3A4 inducers (e.g., rifampin) ↓ exposure.
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Indications
- Neurofibromatosis type 1 (NF1)‑associated plexiform neurofibromas (PN): FDA‑approved for symptomatic, inoperable PN.
- BRAF‑mutant cutaneous melanoma: Under investigation in combination with dabrafenib (clinical trials).
- Solid tumors with RAS/MAPK pathway activation: Investigational use in phase I/II studies (e.g., colorectal cancer, sarcomas).
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Contraindications
| Category | Key Points | |
| Contraindications | Severe hepatic impairment (Child‑Pugh C). | |
| Warnings | Liver Toxicity: ALT/AST > 3× ULN or bilirubin > 2× ULN → hold; discontinue if > 5× ULN. | |
| Cardiovascular: QTc prolongation; use caution in patients with baseline QTc > 450 ms or on other QT‑prolonging drugs. | ||
| Hepatic Metabolism: Co‑administration with strong CYP3A4 inducers/inhibitors requires dose adjustment. |
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Dosing
- NF1‑PN (FDA label):
- Adults: 25 mg orally, twice daily (45 mg for body surface area > 2 m²).
- Pediatric (≥12 yr): 25 mg BID (adjust by BSA).
- Pediatric (2–12 yr): 25 mg BID; weight‑based adjustment as needed.
- Melanoma (combo): 25 mg BID with dabrafenib 150 mg BID orally (dose may be modified by tolerability).
- Administration: Take with a meal to enhance absorption; avoid grapefruit juice.
- Loading Dose: None required.
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Adverse Effects
| Adverse Effect | Frequency | Notes |
| Rash (maculopapular) | < 40 % | Often manageable with topical steroids/antihistamines. |
| Infusion‑related reactions (less frequent) | 2 h post‑dose; premedication with antihistamine may help. | |
| Anemia | 6–12 % | Monitor CBC; transfusion if symptomatic. |
| Peripheral edema | 5–10 % | May require diuretics. |
| ↑Liver enzymes (≥ 3× ULN) | 3–8 % | Close hepatic monitoring; hold dose if > 5× ULN. |
| QTc prolongation | 500 ms. | |
| Severe infections (pneumonitis, sepsis) | Rare | Treat promptly; consider drug interruption. |
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Monitoring
- Baseline: CBC, CMP (incl. LFTs), ECG, serum electrolytes.
- During therapy:
- CBC & CMP bi‑weekly for first 8 weeks, then monthly.
- ECG every 2 weeks for 8 weeks, then as clinically indicated.
- Weight, rash assessment pre‑visit.
- Imaging: MRI/CT of target lesions at 12‑weekly intervals.
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Clinical Pearls
- Food Effect: Taking selumetinib with a high‑fat meal can increase exposure by ~2‑fold—use consistently to avoid peak‑to‑peak variability.
- PK–PD in NF1: The drug’s half‑life (~13 h) aligns with BID dosing, maintaining sufficient MEK inhibition for tumor shrinkage.
- Drug‑Drug Interaction Tip: Patients on ketoconazole, itraconazole, or posaconazole should receive a reduced selumetinib dose (e.g., 12.5 mg BID) to avoid toxicity.
- Adrenal Insufficiency: As MEK inhibition can subtly affect adrenal function, screen high‑risk patients for signs of adrenal crisis.
- Reversible Cardiotoxicity: QTc changes are usually dose‑dependent and reversible; consider adding magnesium sulfate if prolongation persists > 500 ms.
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• *Selumetinib offers a targeted approach for RAS/MAPK‑driven tumors, especially NF1‑associated neurofibromas. Adherence to dosing schedules, vigilant monitoring for hepatotoxicity and cardiac changes, and awareness of drug interactions are essential to maximize efficacy while minimizing harm.*