Absolute Bioavailability of Vemurafenib in Patients With BRAF^V600 Mutation-Positive Malignancies

Vemurafenib is a BRAF kinase inhibitor indicated for the treatment of patients with BRAF^V600 mutation-positive unresectable or metastatic melanoma and Erdheim-Chester disease. This phase 1, open-label, single-arm study was designed to estimate absolute bioavailability of oral vemurafenib at steady state and to characterize the pharmacokinetics of a single intravenous microdose of ¹⁴ C-labeled vemurafenib in patients with BRAF^V600 mutation-positive malignancies. Patients received oral vemurafenib 960 mg twice daily on days 1 through 28, with a single intravenous infusion of ¹⁴ C-labeled vemurafenib solution (3 mL, corresponding to a radioactive dose of 18.5 kBq and a vemurafenib dose of 20 µg) given on the morning of day 21, immediately following the morning dose of oral vemurafenib. A total of 6 patients were enrolled. Four patients who received ¹⁴ C-labeled vemurafenib infusion were included in the pharmacokinetic and bioavailability analyses. Geometric mean absolute bioavailability of oral vemurafenib at steady state, calculated as the ratio of dose-normalized area under the curve during the dosing interval (AUC_τ ) following oral vemurafenib dose to dose-normalized AUC from time 0 extrapolated to infinity (AUC_0-inf ) following vemurafenib intravenous dose, was 57.8%. The majority of radioactivity (geometric mean 41%) was recovered in feces, and a small proportion (geometric mean 1.4%) was recovered in urine. Treatment-emergent adverse events occurred in 5 of 6 (83%) patients and were all grade 1/2 in severity, except for 1 grade-4 anaphylactic reaction occurring during infusion of ¹⁴ C-labeled vemurafenib, which was thought to be related to the excipient polysorbate 80 in the intravenous formulation.