Absorption, Distribution, Metabolism, and Excretion of [(14)C]-Volixibat in Healthy Men: Phase 1 Open-Label Study

BACKGROUND AND OBJECTIVES: Volixibat is a potent inhibitor of the apical sodium-dependent bile acid transporter in development for the treatment of nonalcoholic steatohepatitis. This phase 1, open-label study investigated the absorption, distribution, metabolism, and excretion of [(14)C]-volixibat in heathy men. METHODS: Eligible men (n = 8) aged 18–50 years (body mass index 18.0–30.0 kg/m(2); weight >50 kg) received a single oral dose of [(14)C]-volixibat 50 mg containing ~5.95 µCi radioactivity. The primary objectives were to assess the pharmacokinetics of [(14)C]-volixibat and to determine the total radioactivity in whole blood, plasma, urine, and feces at pre-selected time points over 6 days. The secondary objectives were to characterize metabolites and to assess the safety and tolerability. RESULTS: Low concentrations of volixibat (range 0–0.179 ng/mL) were detected in plasma up to 8 h following administration; the pharmacokinetic parameters could not be calculated. No radioactivity was observed in plasma or whole blood. The percentage (mean ± standard deviation) of total radioactivity in urine was 0.01 ± 0.007%. The vast majority (92.3 ± 5.25%) of volixibat was recovered in feces (69.2 ± 33.1% within 24 h). Unchanged volixibat was the only radioactive component detected in feces. Adverse events were mild in severity and mostly gastrointestinal. Changes in laboratory values were not clinically meaningful. CONCLUSIONS: Following oral administration, [(14)C]-volixibat was excreted unchanged from the parent compound almost exclusively via fecal excretion, indicating that the drug is minimally absorbed. Consistent with other studies, adverse events were primarily gastrointestinal in nature. ClinicalTrials.gov identifier NCT02571192. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s13318-017-0429-7) contains supplementary material, which is available to authorized users.