Absolute Bioavailability and Absorption, Distribution, Metabolism, and Excretion of [¹⁴C]Xevinapant, a Potent, Oral,...

Area of Science:

• Pharmacology
• Drug Metabolism and Pharmacokinetics
• Clinical Pharmacology

Background:

• Xevinapant is a novel small molecule inhibitor of apoptosis proteins (IAPs).
• Understanding the pharmacokinetics, metabolism, and excretion (PME) of xevinapant is crucial for its clinical development.

Purpose of the Study:

• To investigate the PME of xevinapant in healthy male subjects.
• To determine the mass balance, metabolic profile, and absolute oral bioavailability of xevinapant.

Main Methods:

• Phase 1, open-label, 2-part study in healthy males.
• Single oral dose of [¹⁴C]xevinapant (200 mg) for mass balance and metabolism.
• Oral vs. intravenous microtracer doses for absolute oral bioavailability using accelerator mass spectrometry.

Main Results:

• Xevinapant was rapidly absorbed (Tmax 0.5 h) with a half-life of 13.2 h.
• Primary excretion route was fecal (60.2%), followed by urine (33.3%).
• Absolute oral bioavailability was 57.8%; major circulating components were xevinapant and inactive metabolite D-1143-MET1.

Conclusions:

• Xevinapant exhibits favorable pharmacokinetic properties with moderate oral bioavailability.
• The primary elimination pathway is via feces, with significant renal clearance.
• Xevinapant was well tolerated in healthy subjects, supporting further clinical investigation.