Absolute Bioavailability of Vemurafenib in Patients With BRAFV600 Mutation –Positive Malignancies

AbstractVemurafenib is a BRAF kinase inhibitor indicated for the treatment of patients withBRAFV600 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 of14C ‐labeled vemurafenib in patients withBRAFV600 mutation –positive malignancies. Patients received oral vemurafenib 960 mg twice daily on days 1 through 28, with a single intravenous infusion of14C ‐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 received14C ‐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 (AUCτ) following oral vemurafenib dose to dose ‐normalized AUC from time 0 extrapolated to infinity (AUC0 ‐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 ...
Source: Clinical Pharmacology in Drug Development - Category: Drugs & Pharmacology Authors: Tags: Original Manuscript Source Type: research