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Author: Anoma Ranaweera, Medical Writer, Auckland, New Zealand, 2013.
On May 29, 2013, the U. S. Food and Drug Administration (FDA) approved dabrafenib (TAFINLAR™ capsule, GlaxoSmithKline, LLC), for the treatment of patients with non-operable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test. Concurrent with this action, FDA approved the THxID BRAF assay (bioMerieux, Inc. USA) for detection of BRAF V600E. In November 2015, the FDA approved the combination of dabrafenib and trametinib for the treatment of metastatic melanoma. It is approved by MedSafe but not subsidised by PHARMAC in New Zealand.
BRAF mutations occur in 50% of melanomas. BRAF inhibitors such as dabrafenib target mutant BRAF and inhibit the MAPK signalling pathway, which mediates cell growth and survival. They are not effective in non-mutant (wild-type) BRAF tumours.
Dabrafenib is not indicated for the treatment of patients with wild-type BRAF melanoma because of the potential risk of tumour promotion.
The recommended dose is 150 mg orally twice daily taken at least 1 hour before or at least 2 hours after a meal.
In clinical trials, adverse events were common but rarely led to dose reduction or discontinuation.
Most frequent toxicities (ranging from 15% to 33%) included:
Serious adverse events included:
Dabrafenib can cause fetal harm when administered to a pregnant woman (pregnancy Category D). The patient should be warned of the potential hazard to the fetus, if this drug is used during pregnancy or if the patient becomes pregnant while taking this drug.
The safety and effectiveness of dabrafenib has not been established in paediatric patients.
No overall differences in the effectiveness or safety of dabrafeib were observed in the elderly in clinical trials.
No formal pharmacokinetic trial in patients with hepatic or renal impairment has been conducted.
Dabrafenib is primarily metabolised by hepatic enzymes CYP2C8 and CYP3A4. Strong inhibitors or inducers of CYP3A4 or CYP2C8 may increase or decrease, respectively, concentrations of dabrafenib.
If concomitant use of strong inhibitors (e.g. ketoconazole, nefazodone, clarithromycin, gemfibrozil) or strong inducers (e.g., rifampicin, phenytoin, carbamazepine, phenobarbital, St John’s wort) of CYP3A4 or CYP2C8 is unavoidable, patients should be mointored closely for adverse reactions or loss of efficacy.
Coadministration of dabrafenib with warfarin, dexamethasone, or hormonal contraceptives, can also result in decreased concentrations and loss of efficacy.
Drugs that alter the pH of the upper gastrointestinal tract (e.g., proton pump inhibitors, H2-receptor antagonists, antacids) may alter the solubility of dabrafenib and reduce its bioavailability. However, no formal clinical trial has been conducted to evaluate the effect of gastric pH-altering agents on the systemic absorption of dabrafenib.
Dabrafenib and vemurafenib are both selective type 1 BRAF inhibitors with proven efficacy in BRAF V600E metastatic melanoma. They share many attributes, including clinical activity and class-defined toxicity; however, differences between the drugs exist.
In patients with BRAFmut metastatic melanoma, dabrafenib confers high response rates and an improved overall survival rate over chemotherapy, with a mild, manageable toxicity profile. However, the duration of benefit is usually brief because of the development of acquired resistance.
Combination therapies targeting multiple components of cell signalling, such as CombiDT (combination of dabrafenib with trametinib [an MEK inhibitor manufactured by GSK and approved by US FDA]), has shown higher response rates and more durable clinical benefit than dabrafenib monotherapy. The combination of dabrafenib and trametinib, Mekinist™, was provisionally approved by the FDA for unresectable and metastatic melanoma with BRAF V600E or V600K mutations, in 2014 with regular approval in November 2015.
As both drugs target the MAPK pathway, combined blockade may circumvent or delay acquired resistance because of reactivation of the MAPK pathway.
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