Introduction
Selumetinib (brand name Koselugo™) is an oral, small-molecule inhibitor of mitogen-activated protein kinase kinases 1 and 2 (MEK1/2) approved by the U.S. Food and Drug Administration in April 2020. It represents a significant advancement in the treatment of specific genetic disorders, particularly for pediatric patients with neurofibromatosis type 1 (NF1). As a targeted therapy, selumetinib works by interrupting the MAPK pathway, which is dysregulated in certain tumors and genetic conditions.
Mechanism of Action
Selumetinib is a potent and selective allosteric inhibitor of MEK1 and MEK2, key components of the RAS/MAPK signaling pathway. This pathway regulates essential cellular processes including proliferation, differentiation, survival, and angiogenesis. In neurofibromatosis type 1, loss-of-function mutations in the NF1 gene lead to hyperactivation of RAS and subsequent constitutive activation of the MAPK pathway, driving tumor growth. Selumetinib binds to an allosteric site adjacent to the ATP-binding pocket of MEK1/2, inhibiting their kinase activity and downstream phosphorylation of extracellular signal-regulated kinase (ERK). This interruption of aberrant signaling leads to cell cycle arrest and reduced tumor proliferation.
Indications
Selumetinib is FDA-approved for the treatment of pediatric patients aged 2 years and older with neurofibromatosis type 1 (NF1) who have symptomatic, inoperable plexiform neurofibromas. Clinical trials have demonstrated significant tumor volume reduction and clinical benefit in this population. Selumetinib is also under investigation for various oncology indications including KRAS-mutant non-small cell lung cancer, thyroid cancer, and other MAPK pathway-driven malignancies, though these remain investigational uses.
Dosage and Administration
The recommended dosage for pediatric patients with NF1 is 25 mg/m² orally twice daily (approximately every 12 hours) until disease progression or unacceptable toxicity. Administration should be with a light meal (low-fat meal containing approximately 400 calories and 20% fat). The capsules should be swallowed whole with water and not crushed, chewed, or dissolved. Dosage modifications are required for toxicity management, with recommended dose reductions to 20 mg/m² twice daily or 15 mg/m² twice daily. For patients unable to swallow capsules, the contents may be mixed with room temperature water or orange juice. Special populations: No dosage adjustment is recommended for patients with mild hepatic impairment (Child-Pugh A); use with caution in moderate to severe hepatic impairment. Renal impairment studies are limited.
Pharmacokinetics
Absorption: Selumetinib reaches peak plasma concentrations approximately 1.5 hours after administration. Food affects absorption, with a high-fat meal increasing AUC by 79% and Cmax by 70% compared to fasting conditions. Distribution: The mean apparent volume of distribution is 92.6 L. Protein binding is approximately 97%, primarily to albumin and alpha-1 acid glycoprotein. Metabolism: Primarily metabolized via CYP2C19, CYP3A4, and CYP1A2, with N-desmethyl selumetinib (active metabolite) and carboxylic acid metabolite (inactive) as major circulating metabolites. Elimination: The mean elimination half-life is approximately 8 hours. Excretion occurs primarily via feces (69% of dose) with minor renal excretion (19% of dose).Contraindications
Selumetinib is contraindicated in patients with known hypersensitivity to selumetinib or any component of the formulation. There are no other absolute contraindications identified in the prescribing information.
Warnings and Precautions
Cardiac Dysfunction: Selumetinib can cause cardiomyopathy manifested as decreased left ventricular ejection fraction (LVEF). LVEF assessment is required before initiation, during treatment, and as clinically indicated. Ocular Toxicity: Serious ocular toxicities including retinal vein occlusion, retinal pigment epithelial detachment, and uveitis have been reported. Regular ophthalmologic examinations are recommended. Gastrointestinal Toxicity: Diarrhea occurs commonly and may be severe. Prompt management with anti-diarrheal agents and fluid replacement is essential. Skin Toxicity: Severe skin reactions including dermatitis acneiform have been reported. Topical and/or systemic corticosteroids may be required. Creatine Phosphokinase (CPK) Elevation: Selumetinib may cause elevated CPK levels. Monitor CPK levels periodically. Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of reproductive potential to use effective contraception.Drug Interactions
Strong CYP3A4 Inhibitors: Avoid concomitant use with strong CYP3A4 inhibitors (e.g., clarithromycin, itraconazole) as they may increase selumetinib exposure. If unavoidable, reduce selumetinib dose. Strong CYP3A4 Inducers: Avoid concomitant use with strong CYP3A4 inducers (e.g., rifampin, carbamazepine) as they may decrease selumetinib exposure. Acid-Reducing Agents: Proton pump inhibitors may decrease selumetinib absorption. Consider H2-receptor antagonists or antacids as alternatives, with separated administration times. QTc-Prolonging Drugs: Use with caution with drugs known to prolong QTc interval due to potential additive effects.Adverse Effects
Most common adverse reactions (≥40%): Vomiting, rash, abdominal pain, diarrhea, nausea, dry skin, fatigue, musculoskeletal pain, pyrexia, acneiform rash, stomatitis, headache, paronychia, and pruritus. Grade 3-4 adverse reactions: CPK elevation, diarrhea, rash, paronychia, and hypertension. Serious adverse reactions: Cardiomyopathy, ocular toxicity, gastrointestinal toxicity, skin toxicity, and CPK elevation.Monitoring Parameters
- Cardiac function: Echocardiogram or MUGA scan at baseline, every 3 months during first year, then every 6 months
- Ophthalmologic examinations: Baseline and periodically during treatment
- CPK levels: Baseline and periodically during treatment
- Renal function: Serum creatinine at baseline and periodically
- Hepatic function: Liver enzymes at baseline and periodically
- Electrolytes: Particularly magnesium and potassium
- Blood pressure: Regular monitoring
- Growth parameters: In pediatric patients (height, weight)
Patient Education
- Take selumetinib exactly as prescribed with a light meal
- Swallow capsules whole; do not crush, chew, or dissolve
- Report any vision changes, eye pain, or visual disturbances immediately
- Monitor for signs of heart problems (shortness of breath, swelling, fatigue)
- Manage diarrhea promptly with anti-diarrheal medications and maintain hydration
- Use effective contraception during treatment and for 1 week after final dose
- Report skin changes, rash, or nail problems to healthcare provider
- Keep all scheduled appointments for monitoring tests
- Inform all healthcare providers about selumetinib use before starting new medications
References
1. FDA prescribing information: Koselugo (selumetinib) capsules. April 2020. 2. Gross AM, et al. Selumetinib in Children with Inoperable Plexiform Neurofibromas. N Engl J Med. 2020;382(15):1430-1442. 3. Dombi E, et al. Activity of Selumetinib in Neurofibromatosis Type 1-Related Plexiform Neurofibromas. N Engl J Med. 2016;375(26):2550-2560. 4. Jänne PA, et al. Selumetinib plus docetaxel for KRAS-mutant advanced non-small-cell lung cancer: a randomised, multicentre, placebo-controlled, phase 2 study. Lancet Oncol. 2013;14(1):38-47. 5. ClinicalTrials.gov: Various studies including NCT01362803, NCT00726336, and NCT03155620.