Mirdametinib is an investigational oral MEK1/2 inhibitor being developed for NF1-associated plexiform neurofibromas, a rare disorder marked by benign tumor growth along nerves. By targeting the overactive MAPK/ERK pathway, it helps suppress abnormal cell proliferation. The U.S. Food and Drug Administration granted full approval to mirdametinib (brand name Gomekli) on February 11, 2025, for the treatment of adults and children aged 2 years and above diagnosed with neurofibromatosis type 1 (NF1) who have symptomatic plexiform neurofibromas that cannot be fully removed through surgery.

BRAND NAMES:

Gomekli: Gomekli (mirdametinib) is available in two oral formulations: capsules in 1 mg and 2 mg strengths, and dispersible tablets (1 mg) intended for preparation as an oral suspension.

MECHANISM OF ACTION:

Mirdametinib is a selective inhibitor of MEK1 and MEK2, which are dual-specificity kinases in the RAS/RAF/MEK/ERK (MAPK) signaling pathway. In neurofibromatosis type 1 (NF1), loss-of-function mutations in the NF1 gene lead to hyperactivation of RAS and downstream signaling through MEK and ERK, promoting uncontrolled cell proliferation and survival. By inhibiting MEK1/2, Mirdametinib blocks phosphorylation and activation of ERK1/2, thereby reducing cellular proliferation and tumor growth in NF1-associated plexiform neurofibromas and other RAS-driven tumors.

PHARMACOKINETICS:

Absorption

Mirdametinib is rapidly absorbed, reaching peak plasma levels within 1 to 3 hours after oral administration. It has high oral bioavailability and can be taken with or without food.

Distribution

It is highly protein-bound (98%) in plasma and has a moderate volume of distribution, indicating good tissue penetration.

Metabolism

Mirdametinib is primarily metabolized by the liver, mainly via CYP3A4, with minor contributions from CYP2C8 and CYP2C9, followed by glucuronidation.

Elimination

It is eliminated mainly through feces, with minimal renal excretion. It has a half-life of approximately 4 to 6 hours, supporting twice-daily dosing.

DOSAGE AND ADMINISTRATION

Mirdametinib is administered orally twice daily (BID), approximately 12 hours apart, with or without food. The dosage is based on body surface area (BSA) and should be prescribed accordingly for both adult and pediatric patients aged 2 years and older. Treatment is given in 28-day cycles, consisting of 21 consecutive days on treatment followed by 7 days off. Mirdametinib is available as 1 mg and 2 mg capsules, and 1 mg dispersible tablets for oral suspension. Capsules must be swallowed whole, while dispersible tablets can be swallowed or dissolved in 5-10 mL of water and taken as a liquid within 30 minutes. 

CONTRAINDICATIONS:

  • Hypersensitivity to mirdametinib or any excipients
  • Use in pregnancy (may cause fetal harm)
  • Breastfeeding not recommended during and 1 week after treatment
  • Avoid strong CYP3A4 inhibitors/inducers

DRUG INTERACTIONS

  • CYP3A4 Inhibitors: May increase mirdametinib levels (e.g., ketoconazole).
  • CYP3A4 Inducers: May reduce drug efficacy (e.g., rifampin).
  • QT-Prolonging Drugs: Risk of additive QT prolongation (e.g., amiodarone).
  • Gastric pH Modifiers: May affect absorption (e.g., PPIs, H2 blockers).
  • Anticoagulants/Antiplatelets: Possible increased bleeding risk.
  • Transporter Interactions: May affect P-gp/BCRP substrates.

SIDE EFFECTS

  • Diarrhea
  • Fatigue
  • Nausea
  • Vomiting
  • Blurred vision
  • QT prolongation
  • Anemia
  • Elevated liver enzymes
  • Low white blood cell count

TOXICITY

  • Cardiotoxicity: QT prolongation, decreased left ventricular ejection fraction (LVEF).
  • Ocular toxicity: Retinal pigment epithelial detachment, blurred vision.
  • Hepatotoxicity: Elevated liver enzymes (AST, ALT).
  • Dermatologic toxicity: Severe rash or dermatitis in some cases.
  • Gastrointestinal toxicity: Severe diarrhea, nausea, vomiting.
  • Hematologic toxicity: Anemia, neutropenia at higher doses.r doses.