Estado del arte con el tratamiento con inhibidores de BRAF + MEK

PK-PD characteristics

Parameters

Encorafenib

Dabrafenib

Vemurafenib

Implications for

encorafenib

Dissociation T1/2, hours

>30

0.5

Longer dissociation T1/2

translates into prolonged

target suppression

BRAF IC50,

0.0005

0.003

0.001

Lower BRAF and

BRAFV600E IC50

translates into greater

potency at inhibiting

proliferation at lower

concentrations of drug

BRAFV600E, IC50,

0.0004

0.0006

0.0004

Oral absorption

Food intake delayed the

absorption but did not

alter overall drug

exposure

Food decreased the rate

and extent of absorption

Unknown

Can be ingested

regardless of food

consumption

Paradox index (EC80/IC80)

5.5

Higher paradoxical index

translates to a wider

therapeutic window for

achieving tumour

inhibition without

paradoxical ERK

activation

IC50

BRAF

IC50

BRAFV600E

1/2

/IC

1- Stuart DD, et al. AACR. 2012: abstract 3790 2- Ouellet et al., Journal of pharmaceutical sciences, 2013 3- Adelmann et al., 2016, Oncotarget