Dabrafenib

Uses

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

Tafinlar is a kinase inhibitor that was initially indicated as a single agent for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test .

Tafinlar in combination with Trametinib is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations as detected by an FDA-approved test. The use in combination is based on the demonstration of durable response rate. Improvement in disease-related symptoms or overall survival has not been demonstrated for Tafinlar in combination with trametinib .

In May 2018, Tafinlar (dabrafenib) and Mekinist (Trametinib) have been approved in combination to treat anaplastic thyroid cancer caused by an abnormal BRAF V600E gene .

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

How Dabrafenib works

Dabrafenib is an orally bioavailable inhibitor of B-raf (BRAF) protein with antineoplastic activity. Dabrafenib selectively binds to and inhibits the activity of B-raf, which may inhibit the proliferation of tumor cells which contain a mutated BRAF gene. B-raf belongs to the raf/mil family of serine/threonine protein kinases and plays a role in regulating the MAP kinase/Extracellular Signal-regulated Kinases signaling pathway, which may be constitutively activated due to BRAF gene mutations .

Toxicity

LD50 in rats is > 2000 mg/kg .

The most common side effects of Daretinib (Tafinlar) as a single agent include: hyperkeratosis, headache, pyrexia, arthralgia, papilloma, alopecia, and palmar-plantar erythrodysesthesia syndrome .

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 .

The following is a list of toxicities that may occur with the combination of Daretinib 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 .

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

• Avoid grapefruit products. Grapefruit inhibits CYP3A4 metabolism, which may increase the serum levels of dabrafenib.
• Avoid St. John's Wort. This herb induces CYP3A4 metabolism, which may reduce serum levels of dabrafenib.
• Do not take with or immediately after a high-fat meal. Dabrafenib's bioavailability is reduced when taken with a high-fat meal.
• Take on an empty stomach. Take dabrafenib 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 dabrafenib.

In study subjects, administration of dabrafenib with a high-fat meal decreased peak plasma concentration (Cmax) and systemic exposure (AUC) by 51% and 31%, respectively, and delayed median Tmax by approximately 3.6 hours compared to administration in the fasted state.

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

Dabrafenib Drug Interaction

Moderate: paclitaxel protein-bound, doxorubicin, ibuprofen, sulfamethoxazole / trimethoprim, dehydroepiandrosterone, diltiazemUnknown: charcoal, multivitamin with minerals, ubiquinone, copper gluconate, glucose, glycerin, sodium iodide, arginine, levocarnitine, cysteine, metoprolol, metoprolol, pyridoxine, cholecalciferol

Dabrafenib Disease Interaction

Moderate: cardiomyopathy, diabetes, fever, G6PD deficiency, hemorrhage, Dabrafenib – ocular toxicities, lung toxicity

Volume of Distribution

Apparent volume of distribution (Vd/F) = 70.3 L . Distribution to the brain is restricted because dabrafenib is a substrate and undergoes efflux by P-glycoprotein and breast cancer resistance protein .

Elimination Route

After oral administration, median time to achieve peak plasma concentration (Tmax) is 2 hours. Mean absolute bioavailability of oral dabrafenib is 95% .

Half Life

The average terminal half-life of dabrafenib is 8 hours after oral dosing .

Clearance

The clearance of dabrafenib is 17.0 L/h after single dosing and 34.4 L/h after 2 weeks of twice daily dosing

Elimination Route

Fecal excretion is the major route of elimination accounting for 71% of radioactive dose while urinary excretion accounted for 23% of total radioactivity as metabolites only .

Innovators Monograph

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