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 14Cxevinapant 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 14Cxevinapant 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 14Cxevinapant 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.
Ménétrey et al. (Sun,) studied this question.