MEQSEL 2 mg

Indications

• Melanoma with a BRAF V600 mutation
• Advanced non-small cell lung cancer with a BRAF V600 mutation
• Adjuvant treatment of stage III melanoma with a BRAF V600 mutation following complete resection

Dosage

Adults: 2 mg once daily, taken at the same time each day, especially when used in combination with dabrafenib.

Mechanism of action

Trametinib acts as a reversible, highly selective allosteric inhibitor of MEK1 and MEK2. By binding to unphosphorylated forms of MEK1 and MEK2, it inhibits their catalytic activity and prevents phosphorylation, thereby blocking the downstream signaling in the MAPK pathway. This disruption halts the dysregulated proliferation and survival of tumor cells associated with BRAF mutations in various cancers.

Pharmacodynamics

Trametinib has been shown to inhibit cell growth in various tumors that carry BRAF V600 mutations both in vitro and in vivo. It is commonly used in combination with dabrafenib, a BRAF inhibitor, to counteract mechanisms of resistance that may arise in BRAF-mutant cancers, such as the reactivation of the MAPK pathway through EGFR signaling.

Pharmacokinetics

Trametinib is administered orally and exhibits a half-life that allows for once-daily dosing. It requires storage in a refrigerator and has specific recommendations for monitoring liver function and cardiac health during treatment. The pharmacokinetic profile may be affected by hepatic and renal function, necessitating caution in patients with moderate to severe impairment.

Contra-indications

• Hypersensitivity to trametinib or any of its components
• Pregnancy
• Breastfeeding

Adverse effects

• Skin rashes
• Mucositis
• Nausea
• Edema
• Respiratory disorders
• Hyponatraemia
• Hypotension
• Leucopenia
• Muscle spasms
• Myocarditis
• Neutropenia
• Night sweats
• Thrombocytopenia
• Rhabdomyolysis
• Retinal detachment
• Heart failure

Interactions

• Verapamil (increases concentration)
• Ciclosporin (increases concentration)
• Ivacaftor (increases concentration)
• Lapatinib (increases concentration)
• Macrolides (increases concentration)
• Neratinib (increases concentration)
• Ranolazine (increases concentration)
• Rucaparib (increases concentration)
• Calcium channel blockers (increases concentration)
• Vandetanib (increases concentration)

Precautions

• Caution in patients with moderate to severe hepatic impairment
• Caution in patients with severe renal impairment
• Monitoring of blood pressure at baseline and during treatment
• Evaluation of left ventricular ejection fraction prior to and during treatment
• Monitoring of liver function every 4 weeks for 6 months after treatment initiation

Pregnancy

Manufacturer advises avoiding use due to potential toxicity observed in animal studies.

Breast-feeding

Manufacturer advises avoiding use as no information is available on excretion in breast milk.

Storage

Store in a refrigerator (2–8 °C); once opened, the bottle may be stored for 30 days at not more than 30 °C.

Formulations

• 2 mg oral capsule

Mechanism of action

The mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinases (ERK) pathway, also known as the RAS-RAF-MEK-ERK pathway, activates a cascade of cell surface receptors and intracellular downstream signalling molecules. Activated RAS protein activates RAF, a serine/threonine kinase that activates other downstream proteins such as mitogen-activated extracellular signal-regulated kinase 1 (MEK1) and MEK2. MEKs then activates ERK, which works on several target proteins and nuclear transcription factors that regulate cell proliferation, differentiation, survival, and growth. ARAF, BRAF, and CRAF are three isoforms of RAF identified in humans. In particular, BRAF is known to be the most critical activator in melanoma. Certain cancers, such as melanoma, are associated with BRAF mutations, with one study suggesting that BRAF is mutated in about 50% of melanoma tumours. BRAF V600E and V600K mutations account for 95% of BRAF mutations. These BRAF mutations cause constitutive activation of the RAS-RAF-MEK-ERK pathway, leading to dysregulated proliferation and survival of tumour cells. Trametinib is a reversible, highly selective, allosteric inhibitor of MEK1 and MEK2. By binding to unphosphorylated MEK1 and MEK2 with high affinity, trametinib blocks the catalytic activity of MEKs. It also maintains MEK in an unphosphorylated form, preventing phosphorylation and activation of MEKs. _In vitro_ studies suggest that dual inhibition of the MAPK pathway by MEK and B-RAF inhibitors is associated with a synergistic effect and improved therapeutic efficacy in cancers compared to using either drug alone. The combined use of trametinib and dabrafenib, a BRAF inhibitor, results in more significant growth inhibition of BRAF V600 mutation-positive tumour cell lines _in vitro_ and prolonged inhibition of tumour growth in BRAF V600 mutation-positive tumour xenografts compared to either drug alone. The combined inhibition of MEK by trametinib and RAF by dabrafenib delays the emergence of resistance _in vivo_ in BRAF V600 mutation-positive melanoma xenografts.

Pharmacodynamics

Trametinib inhibits cell growth of various BRAF V600 mutation-positive tumours _in vitro_ and _in vivo_. Trametinib is often used in combination with dabrafenib, a BRAF inhibitor. In BRAF-mutant colorectal cancer, induction of EGFR-mediated MAPK pathway re-activation has been identified as a mechanism of intrinsic resistance to BRAF inhibitors.