Singapore Drugs Database

Indication

Trametinib is indicated for the treatment of unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test [FDA]. In May 2018, it was approved for use with [DB08912] for the treatment of treat anaplastic thyroid cancer caused by an abnormal BRAF V600E gene [L2726].

Mechanism of Action

Trametinib is a reversible, allosteric inhibitor of mitogen-activated extracellular signal regulated kinase 1 _(MEK1)_ and _MEK2_ activation and of_ MEK1_ and _MEK2_ kinase activity. MEK proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway, which promotes cellular proliferation. Trametinib helps with melanoma with the BRAF V600E or V600K as the mutation results in the constitutive activation of the BRAF pathway which includes MEK1 and MEK2 [FDA label].

Pharmacokinetics

Absorption

Trametinib is readily absorbed. When an oral administration of trametinib was given to patients with BRAF V600 mutation-positive melanoma, peak plasma concentration occurred 1.5 hours post-dose (Tmax). A single 2 mg oral dose has a bioavailability of 72%. When a dose of 2mg/day is given, the peak plasma concentration (Cmax) is 22.2 ng/mL [FDA label].

Distribution

Apparent volume of distribution (Vd/F) = 214 L [FDA label]

Metabolism

Trametinib is metabolized predominantly via deacetylation alone or with mono-oxygenation or in combination with glucuronidation biotransformation pathways in vitro. Deacetylation is likely mediated by hydrolytic enzymes, such as carboxyl-esterases or amidases. The cytochrome P450 enzyme system is not involved with the metabolism of trametinib. The predominant circulating component in the plasma is the parent drug [FDA label].

Elimination

Clearance

Apparent clearance = 4.9 L/h [FDA label]

Toxicity

Most common adverse reactions (≥20%) for trametinib include rash, diarrhea, and lymphedema [FDA label]. The most common adverse reactions (≥20%) for Tafinlar in combination with Trametinib are pyrexia, chills, fatigue, rash, nausea, vomiting, diarrhea, abdominal pain, peripheral edema, cough, headache, arthralgia, night sweats, decreased appetite, constipation, and myalgia [FDA Label]. The following is a list of toxicities that may occur with the combination of Dabrafenib and Trametinib: **New primary malignancies**: These may occur when Tafinlar is administered as a single agent or in combination with Trametinib. Monitor patients for new malignancies prior to initiation of therapy, while on therapy, and following discontinuation of TAFINLAR or the combination therapy. Tumor Promotion in BRAF Wild-Type Melanoma: Increased cell proliferation can occur with BRAF inhibitors [FDA Label]. **Hemorrhage**: Major hemorrhagic events can occur in patients receiving TAFINLAR in combination with trametinib. Monitor for signs and symptoms of bleeding [FDA Label]. **Venous Thromboembolism**: Deep vein thrombosis and pulmonary embolism can occur in patients receiving the drug combination [FDA Label]. **Cardiomyopathy**: Assess LVEF before treatment with TAFINLAR in combination with trametinib, after one month of treatment, then every 2 to 3 months thereafter [FDA Label]. **Ocular toxicities**: Perform an ophthalmologic evaluation for any visual disturbances [FDA Label]. **Serious Febrile Reactions**: Incidence and severity of pyrexia are increased with TAFINLAR in combination with trametinib [FDA Label]. **Serious Skin Toxicity**: Monitor for skin toxicities and for secondary infections. Discontinue for intolerable Grade 2, or Grade 3 or 4 rash not improving within 3 weeks despite the interruption of TAFINLAR [FDA Label]. **Hyperglycemia**: Monitor serum glucose levels in patients with pre-existing diabetes or hyperglycemia [FDA Label]. **Glucose-6-Phosphate Dehydrogenase Deficiency**: Closely monitor for hemolytic anemia [FDA Label]. **Embryofetal Toxicity**: Can cause fetal harm. Advise females of reproductive potential of potential risk to a fetus. TAFINLAR may render hormonal contraceptives less effective and an alternative method of contraception should be used [FDA Label].

Active Ingredient/Synonyms

Tramétinib | Trametinib | Trametinibum | Trametinib |