A Phase 1, Open-Label Study in Healthy Subjects to Evaluate the Absolute Bioavailability of AG-221 by a Microtracer Approach

INTRODUCTION: The purpose of this study was to evaluate the absolute bioavailability (BA) of AG-221 following a single oral dose of 100 mg AG-221 and an intravenous (IV) dose of ~ 100 μg AG-221 containing approximately 300 nCi of [(14)C]-AG-221. METHODS: This was a phase 1, open-label study. Six subjects who met all of the inclusion criteria and none of the exclusion criteria were enrolled in the study. After an overnight fast of at least 10 h, the subjects received an oral dose (coated tablet) of 100 mg of AG-221 at 0 h on dosing day. Four hours after the oral dose, the subjects received 100 μg AG-221 containing ~ 300 nCi of [(14)C]-AG-221 administered as an IV bolus. Blood samples were collected and analyzed for plasma concentrations of AG-221 and [(14)C]-AG-221 using a validated liquid chromatography with tandem mass spectrometry (LC–MS/MS) system and high-performance liquid chromatography (HPLC) fractionation followed by accelerator mass spectrometry analysis (AMS), respectively. Safety was evaluated throughout the study. RESULTS: The absolute BA after a 100-mg oral dose of AG-221 was measured as 57.2%. While the total clearance was 1.37 L/h, ~ 1/60 of the liver blood flow in a typical 70-kg human subject, the first-pass extraction was estimated to be less than 2%, assuming that the total clearance was entirely due to liver metabolism. Thus, the fraction of the AG-221 dose absorbed was at least 50%. AG-221 was safe and well tolerated when given under fasted conditions in a single 100-mg dose as a coated tablet with a microtracer [(14)C]-AG-221 solution, as few drug-related treatment-emergent adverse events (TEAEs) were reported. No clinically significant changes or findings were noted in the clinical laboratory evaluations, vital sign measurements, and electrocardiograms (ECGs) performed during this study. CONCLUSIONS: In healthy subjects under fasting conditions, the absolute BA following oral administration of a 100-mg AG-221 tablet was 57.2%. AG-221 was safe and well tolerated in healthy male subjects when administered as a single 100-mg film-coated tablet plus 100 µg [(14)C]-AG-221 given intravenously. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02443168. FUNDING: Celgene Corporation.