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The SARfaris: GPCR, Kinase, ADME

Tuesday, 4 June 2013

New Drug Approvals 2013 - Pt. IX - Dabrafenib mesylate (Tafinlar®)

ATC code: L01XE15
Wikipedia: Dabrafenib

On May 29th 2013 the FDA approved dabrafenib mesylate (trade name: Tafinlar®, research codes GSK-2118436A and GSK-2118436B) for the treatment of patients with unresectable metastatic melanoma harbouring the BRAF V600E mutation. In clinical trials, dabrafenib showed improved progression-free survival (PFS) over the comparator dacarbazine (median PFS 5.1 months for dabrafenib compared to 2.7 months for dacarbazine). Moreover, in a multicentre open-label Phase II trial dabrafenib showed effectiveness on brain metastases of melanoma regardless of whether the patients had been previously treated.

As with the previously approved BRAF inhibitor, vemurafenib, the major side effect of dabrafenib is the emergence of malignant cutaneous squamous cell carcinomas and keratoacanthomas.

The main molecular target for dabrafenib is the human mutant serine/threonine kinase, BRAF (Uniprot for wild type protein: P15056). Dabrafenib potently inhibits multiple mutant BRAF species including V600E at 0.65 nM, V600K at 0.5 nM and V600D at 1.84 nM. It also inhibits wild type BRAF at 3.2 nM and wild type CRAF at 5 nM.

Dabrafenib is administered orally as capsules containing the dabrafenib mesylate salt. Dabrafenib freebase (ChEMBL:CHEMBL2028663) has a molecular weight of 519.6 and AlogP of 5.38. The molecular formula of dabrafenib is C23H20F3N5O2S2. After oral administration, the median time to reach peak plasma concentration (Tmax) is 2 hours; the mean absolute bioavailability is 95% and the mean terminal half-life is 8 hours after oral administration.

Tafinlar® is produced by Glaxosmithkline

The full Prescribing Information is here


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