Encorafenib (LGX818) is a promising BRAFV600E inhibitor that has efficacy 
against metastatic melanoma. To better understand its pharmacokinetics, we 
studied its interactions with the multidrug efflux transporters ABCB1 and ABCG2 
and the multidrug metabolizing enzyme CYP3A. In polarized MDCK-II cells, 
encorafenib was efficiently transported by canine and human ABCB1 and ABCG2 and 
by mouse Abcg2. Upon oral administration to wild-type, Abcb1a/1b-/-, Abcg2-/-, 
and Abcb1a/1b;Abcg2-/- mice, encorafenib was absorbed very quickly and to very 
high plasma levels, but without clear changes in oral availability between the 
strains. Upon oral or intravenous administration, encorafenib brain accumulation 
was markedly increased in Abcb1a/1b;Abcg2-/- mice and to a lesser extent in 
Abcb1a/1b-/- mice. However, absolute brain concentrations and brain-to-plasma 
ratios remained very low in all strains, indicating intrinsically poor brain 
penetration of encorafenib. Upon intravenous administration, Abcb1a/1b;Abcg2-/- 
mice showed somewhat reduced plasma elimination of encorafenib compared to 
wild-type mice, and lower accumulation of the drug in the intestinal tract, 
suggesting a limited role for these transporters in intestinal elimination of 
the drug. In Cyp3a-/- mice plasma levels of encorafenib were not markedly 
increased, suggesting a limited impact of Cyp3a on encorafenib oral 
availability. The low brain penetration of encorafenib might limit its efficacy 
against malignancies positioned behind a functional blood-brain barrier, but its 
oral bioavailability and distribution to other tested organs (liver, kidney, 
spleen, testis) was high.