Dabrafenib

In this article, we will discuss Dabrafenib (Mechanism of Action). So, let’s get started.

Mechanism of Action

Dabrafenib is an inhibitor of some mutated forms of BRAF kinases with in vitro IC50 values of 0.65, 0.5, and 1.84 nM for BRAF V600E, BRAF V600K, and BRAF V600D enzymes, respectively. Dabrafenib also inhibits wild-type BRAF and CRAF kinases with IC50 values of 3.2 and 5.0 nM, respectively, and other kinases such as SIK1, NEK11, and LIMK1 at higher concentrations. Some mutations in the BRAF gene, including those that result in BRAF V600E, can result in constitutively activated BRAF kinases that may stimulate tumor cell growth. Dabrafenib inhibits cell growth of various BRAF V600 mutation-positive tumors in vitro and in vivo.

Dabrafenib and trametinib target two different kinases in the RAS/RAF/MEK/ERK pathway. Use of dabrafenib and trametinib in combination resulted in greater growth inhibition of BRAF V600 mutation-positive tumor cell lines in vitro and prolonged inhibition of tumor growth in BRAF V600 mutation positive tumor xenografts compared with either drug alone.

Pharmacodynamics

Cardiac Electrophysiology

The potential effect of Dabrafenib on QT prolongation was assessed in a dedicated multiple-dose study in 32 patients with BRAF V600 mutation-positive tumors. No large changes in the mean QT interval (i.e., > 20 ms) were detected with dabrafenib 300 mg administered twice daily (two times the recommended dosage). In clinical trials, QTc (heart rate-corrected QT) prolongation to ≥ 500 ms occurred in 0.8% (2/264) of patients receiving Dabrafenib plus trametinib and in 1.5 % (4/264) of patients receiving Dabrafenib as a single agent. The QTc was increased > 60 ms from baseline in 3.8% (10/264) of patients receiving Dabrafenib plus trametinib and 3% (8/264) of patients treated with Dabrafenib as a single agent.

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