Singapore Drugs Database

Indication

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 [FDA label]. Tafinlar in combination with [DB08911] 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 [FDA label]. In May 2018, Tafinlar (dabrafenib) and Mekinist ([DB08911]) have been approved in combination to treat anaplastic thyroid cancer caused by an abnormal BRAF V600E gene [L2712].

Mechanism of Action

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 [FDA label].

Pharmacokinetics

Absorption

After oral administration, median time to achieve peak plasma concentration (Tmax) is 2 hours. Mean absolute bioavailability of oral dabrafenib is 95% [L2711].

Distribution

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

Metabolism

Dabrafenib is metabolized in the liver. The biotransformation process of this drug is primarily regulated by _CYP2C8_ and _CYP3A4_ to form _hydroxy-debrafenib_. This metabolite is further oxidized via CYP3A4 to form _carboxy-dabrafenib_ and subsequently excreted in bile and urine. Carboxy-dabrafenib can also undergo decarboxylation to form _desmethyl-dabrafenib_, which may be reabsorbed from the gastrointestinal tract. _Desmethyl-dabrafenib_ is further metabolized by CYP3A4 to oxidative metabolites [L2711], [FDA label].

Elimination

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 [FDA label]

Toxicity

LD50 in rats is > 2000 mg/kg [MSDS]. The most common side effects of Daretinib (Tafinlar) as a single agent include: hyperkeratosis, headache, pyrexia, arthralgia, papilloma, alopecia, and palmar-plantar erythrodysesthesia syndrome [FDA label]. The most common adverse reactions (≥20%) for Tafinlar in combination with [DB08911] 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 Daretinib and [DB08911]: **New primary malignancies**: These may occur when Tafinlar is administered as a single agent or in combination with [DB08911]. 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

Dabrafenib | Dabrafenib |