Usage
Trametinib is prescribed for the treatment of various cancers with a BRAF V600E or V600K mutation, including:
- Unresectable or metastatic melanoma
- Adjuvant treatment of melanoma with lymph node involvement after complete resection
- Metastatic non-small cell lung cancer (NSCLC)
- Locally advanced or metastatic anaplastic thyroid cancer (ATC) with no satisfactory locoregional treatment options.
- Unresectable or metastatic solid tumors in adults and children 6 years and older who have progressed following prior treatment and have no satisfactory alternative treatment options.
Pharmacological Classification: Kinase inhibitor, specifically a MEK1/2 inhibitor.
Mechanism of Action: Trametinib inhibits MEK1 and MEK2, key components of the MAPK signaling pathway, which plays a crucial role in cell growth and proliferation. Inhibiting MEK disrupts this pathway, particularly in cancer cells with BRAF V600 mutations, thereby suppressing tumor growth.
Alternate Names
International Nonproprietary Name (INN): Trametinib
Brand Names: Mekinist
How It Works
Pharmacodynamics: Trametinib selectively inhibits MEK1 and MEK2 kinases. This leads to a downstream blockade of the MAPK pathway, impacting cellular processes including cell growth, proliferation, differentiation, and survival, particularly in tumor cells with BRAF V600 mutations.
Pharmacokinetics:
- Absorption: Trametinib is absorbed orally, and its absorption is affected by food intake. Taking it without food results in higher serum drug levels.
- Metabolism: Primarily hepatic metabolism. However, specific details about the metabolic pathways (e.g., the involvement of specific CYP enzymes) are not widely available.
- Elimination: Primarily fecal excretion (over 80%), with less than 19% eliminated in the urine.
Mode of Action: Trametinib binds to and inhibits MEK1/2, hindering the phosphorylation and activation of ERK1/2. This disruption of the MAPK pathway leads to decreased tumor cell growth and survival.
Receptor Binding/Enzyme Inhibition: Trametinib specifically targets and inhibits MEK1 and MEK2 enzymes.
Elimination Pathways: Mainly fecal excretion, with minimal urinary excretion.
Dosage
Standard Dosage
Adults: 2 mg orally once daily, taken at least one hour before or two hours after a meal.
Children (6 to 17 years old):
- 26-37 kg: 1 mg orally once daily.
- 38-50 kg: 1.5 mg orally once daily.
- 51 kg or more: 2 mg orally once daily.
A recommended dosage has not been established for children younger than 6 years of age or weighing less than 26 kg.
Special Cases:
- Elderly Patients: No initial dose adjustment is necessary but more frequent dose adjustments may be needed due to potential age-related changes in drug clearance.
- Patients with Renal Impairment: No dose adjustment is required for mild or moderate impairment. For severe renal impairment, use with caution, as data is limited.
- Patients with Hepatic Dysfunction: No dose adjustment is required for mild impairment. Use with caution in moderate or severe hepatic impairment, as data is limited.
- Patients with Comorbid Conditions: Close monitoring and potential dose adjustments might be necessary depending on the specific comorbidity.
Clinical Use Cases
Trametinib’s primary use is in targeted therapy for BRAF V600 mutation-positive cancers. It’s not typically used in settings like intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations like status epilepticus or cardiac arrest.
Dosage Adjustments
Dose reductions may be required based on individual patient tolerability and the development of adverse events. Consider factors like renal/hepatic dysfunction, other comorbid conditions, and concomitant medications when adjusting the dose.
Side Effects
Common Side Effects:
Rash, diarrhea, edema, fatigue, nausea, vomiting, alopecia, hypertension, constipation, headache, abdominal pain, dry skin, dry mouth, changes in taste, joint or muscle pain.
Rare but Serious Side Effects:
Bleeding (including gastrointestinal and pulmonary hemorrhage), cardiomyopathy (decreased left ventricular ejection fraction), ocular toxicities (retinal vein occlusion, retinal detachment), pulmonary abnormalities (interstitial lung disease, pneumonitis), severe skin reactions (Stevens-Johnson syndrome), secondary malignancies, pancreatitis.
Long-Term Effects:
Potential long-term effects can include cardiac dysfunction, ocular damage, and the development of secondary malignancies.
Adverse Drug Reactions (ADR):
Severe bleeding, cardiomyopathy, ocular toxicity, pulmonary toxicity, severe skin reactions.
Contraindications
Hypersensitivity to trametinib or any of its components. It should not be used in patients with colorectal cancer due to inherent resistance to BRAF inhibition. Patients who have progressed on prior BRAF inhibitor therapy are also not candidates for trametinib.
Drug Interactions
Trametinib has moderate drug interactions with numerous medications, including several kinase inhibitors, antifungals, and other targeted therapies. Consult a comprehensive drug interaction resource for the most up-to-date information. Concurrent use with dabrafenib may reduce the effectiveness of hormonal contraceptives, necessitating alternative birth control methods.
Pregnancy and Breastfeeding
Pregnancy Safety Category: D (Australia); Not Assigned (US FDA - older system has been phased out). Trametinib can cause fetal harm. Effective contraception must be used during treatment and for four months after the last dose.
Breastfeeding: Trametinib should not be used during breastfeeding and for four months after the final dose. It is unknown if trametinib is present in human milk.
Drug Profile Summary
- Mechanism of Action: MEK1/2 inhibitor, disrupting the MAPK pathway.
- Side Effects: Rash, diarrhea, edema, fatigue, bleeding, cardiac dysfunction, ocular toxicity, pulmonary toxicity.
- Contraindications: Hypersensitivity, colorectal cancer, prior progression on BRAF inhibitor therapy.
- Drug Interactions: Numerous moderate interactions, including those affecting hormonal contraceptives. Consult drug interaction databases.
- Pregnancy & Breastfeeding: Contraindicated.
- Dosage: Adults: 2 mg OD; Pediatrics: weight-based dosing.
- Monitoring Parameters: LVEF, eye exams, pulmonary function tests, blood pressure, blood glucose.
Popular Combinations
Trametinib is frequently used in combination with Dabrafenib, a BRAF inhibitor, for synergistic anticancer effects in BRAF V600 mutation-positive cancers.
Precautions
Screen patients for pre-existing cardiac, pulmonary, ocular, and hepatic conditions. Monitor closely for adverse effects. Pregnant or breastfeeding women should not handle the drug.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Trametinib?
A: Adults: 2 mg orally once daily. Children (6 to 17 years old): weight-based dosing (1 mg, 1.5 mg, or 2 mg daily).
Q2: How should Trametinib be taken?
A: Orally, on an empty stomach, at least one hour before or two hours after a meal.
Q3: What are the most common side effects of Trametinib?
A: Rash, diarrhea, edema, fatigue, nausea, vomiting.
A: Severe bleeding, signs of heart failure, changes in vision, new or worsening cough or shortness of breath, severe skin reactions.
Q5: Can Trametinib be used during pregnancy or breastfeeding?
A: No, it is contraindicated in both pregnancy and breastfeeding due to the risk of fetal harm and potential neonatal exposure.
Q6: What should be monitored in patients taking Trametinib?
A: Left ventricular ejection fraction (LVEF), eye exams for ocular toxicity, pulmonary function tests, blood pressure, and blood glucose.
Q7: Does Trametinib interact with other medications?
A: Yes, Trametinib has potential interactions with numerous other medications. Consult a comprehensive drug interaction resource for specific information.
A: Trametinib is primarily metabolized in the liver and excreted mainly in the feces.
Q9: What cancers is Trametinib used to treat?
A: Trametinib is primarily used to treat various BRAF V600-mutant cancers, such as melanoma, NSCLC, and anaplastic thyroid cancer.
Q10: What is the role of BRAF V600 mutation testing in patients considered for Trametinib therapy?
A: BRAF V600 mutation testing using a validated test is essential before starting Trametinib, as the drug’s efficacy is specific to tumors with this mutation. Trametinib is not indicated for patients who test negative for the BRAF V600 mutation.
