Impact of posaconazole and diltiazem on pharmacokinetics of encorafenib, a BRAF V600 kinase inhibitor for melanoma and colorectal cancer with BRAF mutations

Encorafenib is a potent and selective ATP competitive inhibitor of BRAF V600–mutant kinase approved for patients with BRAF‐mutant melanoma and colorectal cancer. Encorafenib is mainly metabolized by cytochrome P450 (CYP) 3A4 in vitro and may be susceptible to drug–drug interactions when co‐administered with CYP3A inhibitors or inducers. The primary objective was to assess the impact of the strong CYP3A inhibitor posaconazole (part 1) and the moderate CYP3A and P‐gp inhibitor diltiazem (part 2) on encorafenib pharmacokinetics in healthy volunteers following a single 50‐mg dose. A total of 32 participants were enrolled (16 each in parts 1 and 2). The area under the curve extrapolated to infinity (AUCinf) and maximum plasma concentration (Cmax) geometric mean for encorafenib increased by 183% and 68.4%, respectively, when co‐administered with posaconazole. Apparent encorafenib clearance decreased from 26.0 to 9.2 L/h when coadministered with posaconazole, and plasma terminal half‐life (t½) of encorafenib increased from 4.3 to 7.3 h. The AUCinf and Cmax geometric mean for encorafenib increased by 83.0% and 44.7%, respectively, when co‐administered with diltiazem. Similarly, the apparent encorafenib clearance decreased from 29.0 to 16.0 L/h when co‐administered with diltiazem, and plasma t½ of encorafenib increased from 6.6 to 7.9 h. There were no deaths, serious adverse events (AEs), or patient discontinuations due to AEs in parts 1 or 2. The most frequently reported treatment‐related AEs were erythema (n = 14; 88%) and headache (n = 11; 69%) in part 1 and headache (n = 7; 44%) in part 2. The results of this study indicate that co‐administration of encorafenib with strong or moderate CYP3A4 inhibitors should be avoided.