The absorption, distribution, metabolism, excretion, and pharmacokinetic properties of the pan-rapidly accelerated fibrosarcoma (RAF) inhibitor naporafenib in healthy subjects: An absolute bioavailability and mass balance study.

The absorption, distribution, metabolism, and excretion study and the absolute bioavailability study were conducted to determine the pharmacokinetics, mass balance, metabolite profile, and absolute bioavailability of naporafenib, a selective pan-rapidly accelerated fibrosarcoma (RAF) inhibitor. This was an open-label, single-center, 2-part, fixed-sequence study. In part 1, a tracer [14C]-naporafenib was administered intravenously with a single 200-mg oral dose of naporafenib to 8 healthy male participants to assess the absolute bioavailability and pharmacokinetics of naporafenib. After a 15-day washout, a single 200-mg/500-μCi oral dose of [14C]-naporafenib was administered to the same participants in part 2 to investigate the mass balance and metabolism of naporafenib. The absolute bioavailability was determined to be 39.6%. The geometric mean clearance was 7.58 L/h, volume of distribution was 162 L, and terminal half-life was 18.1 hours. A near complete recovery (94.0%) of administered radioactivity was achieved, with 78.8% of the dose excreted in feces and 15.2% of dose recovered in the urine. The metabolism of naporafenib involved multiple primary metabolic pathways that included amide hydrolysis, oxidation, glucuronidation, dealkylation, and dehydrogenation, with secondary hydrolysis, N-acetylation, N-methylation, reduction, glucuronidation, and oxidation. No metabolite exceeded 10% of total circulating drug-related radioactivity. There were no major/disproportionate or unique human metabolites. No metabolites warranted future evaluation given low abundance. SIGNIFICANCE STATEMENT: This study provides a detailed understanding of the pharmacokinetics, disposition, and metabolism of naporafenib after oral and microtracer intravenous administration in healthy participants. This knowledge will guide future nonclinical and clinical studies evaluating drug-drug interactions, organ dysfunction, and safety of metabolites.