Trametinibum

Uses

Trametinibum is a kinase inhibitor used to treat patients with specific types of melanoma, non-small cell lung cancer, and thyroid cancer.

Trametinibum 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 Dabrafenib for the treatment of treat anaplastic thyroid cancer caused by an abnormal BRAF V600E gene .

Trametinibum is also used to associated treatment for these conditions: Metastatic Melanoma, Unresectable Melanoma

How Trametinibum works

Trametinibum 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. Trametinibum 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 .

Toxicity

Most common adverse reactions (≥20%) for trametinib include rash, diarrhea, and lymphedema .

The most common adverse reactions (≥20%) for Tafinlar in combination with Trametinibum are pyrexia, chills, fatigue, rash, nausea, vomiting, diarrhea, abdominal pain, peripheral edema, cough, headache, arthralgia, night sweats, decreased appetite, constipation, and myalgia .

The following is a list of toxicities that may occur with the combination of Dabrafenib and Trametinibum:

New primary malignancies: These may occur when Tafinlar is administered as a single agent or in combination with Trametinibum. 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 .

Hemorrhage: Major hemorrhagic events can occur in patients receiving TAFINLAR in combination with trametinib. Monitor for signs and symptoms of bleeding .

Venous Thromboembolism: Deep vein thrombosis and pulmonary embolism can occur in patients receiving the drug combination .

Cardiomyopathy: Assess LVEF before treatment with TAFINLAR in combination with trametinib, after one month of treatment, then every 2 to 3 months thereafter .

Ocular toxicities: Perform an ophthalmologic evaluation for any visual disturbances .

Serious Febrile Reactions: Incidence and severity of pyrexia are increased with TAFINLAR in combination with trametinib .

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 .

Hyperglycemia: Monitor serum glucose levels in patients with pre-existing diabetes or hyperglycemia .

Glucose-6-Phosphate Dehydrogenase Deficiency: Closely monitor for hemolytic anemia .

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 .

Food Interaction

• Take separate from meals. Take at least one hour before or two hours after a meal.

[Moderate] ADJUST DOSING INTERVAL: Food may reduce as well as delay the absorption of trametinib.

In study subjects, administration of a single dose of trametinib with a high-fat, high-calorie meal decreased peak plasma concentration (Cmax) and systemic exposure (AUC) by 70% and 24%, respectively, and delayed Tmax by approximately 4 hours compared to administration in the fasted state.

MANAGEMENT: Trametinibum should be taken at least 1 hour before or 2 hours after a meal.

Trametinibum Disease Interaction

Moderate: lung toxicity, cardiomyopathy, GI perforation, hemorrhage, hepatic impairment, hyperglycemia, ocular toxicities, renal impairment, venous thromboembolism

Volume of Distribution

Apparent volume of distribution (Vd/F) = 214 L

Elimination Route

Trametinibum 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 .

Half Life

Elimination half-life = 3.9-4.8 days .

Clearance

Apparent clearance = 4.9 L/h

Elimination Route

80% of the dose is excreted in the feces. Label.

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