Absolute Bioavailability and Absorption, Distribution, Metabolism, and Excretion of [ ¹⁴ C]Xevinapant, a Potent, Oral, Small‐Molecule IAP Inhibitor

This Phase 1, open-label, 2-part, single-dose study aimed to investigate the pharmacokinetics, metabolism, and excretion of xevinapant, a small molecule inhibitor of apoptosis proteins (IAPs), in healthy male subjects. Part 1 focused on determining the mass balance recovery, pharmacokinetics, and metabolic profile of [¹⁴C]xevinapant following a single oral dose of 200 mg. Part 2 aimed to determine the absolute oral bioavailability of xevinapant by evaluating the pharmacokinetics of an oral dose of 200 mg xevinapant in comparison to an intravenous microtracer dose of [¹⁴C]xevinapant using accelerator mass spectrometry. After oral administration, xevinapant was rapidly absorbed, with a median time to maximum concentration of 0.5 h and a geometric mean half-life of 13.2 h. The principal route of excretion of drug-related material was fecal, accounting for 60.2% of the administered dose, while 33.3% was excreted in urine. Renal clearance accounted for 18.4% of total clearance. In addition to xevinapant, seven metabolites were structurally characterized in the samples analyzed. The principal route of metabolism was dealkylation to form metabolite D-1143-MET1, with secondary metabolism by oxidation. The major circulating components in plasma were xevinapant and D-1143-MET1 (inactive on IAPs), which represented 28% and 42% of the total drug-related exposure, respectively. The absolute oral bioavailability of xevinapant was determined to be 57.8%. The clearance of [¹⁴C]xevinapant was 12.2 L/h and the volume of distribution at steady-state was 75.3 L. Xevinapant was well tolerated in healthy male subjects, with no clinically significant findings in clinical laboratory evaluations, vital signs, ECG, or physical examinations.