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

Abstract

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 [14C]-volixibat in heathy men.

Methods: Eligible men (n = 8) aged 18-50 years (body mass index 18.0-30.0 kg/m2; weight >50 kg) received a single oral dose of [14C]-volixibat 50 mg containing ~5.95 µCi radioactivity. The primary objectives were to assess the pharmacokinetics of [14C]-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, [14C]-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.

Conflict of interest statement

Funding

This research was funded by Shire Human Genetic Therapies Inc. (Lexington, MA, USA). Shire develops and markets treatments for liver diseases, including volixibat. Under the direction of the authors, Dr. E. Gandhi of Oxford PharmaGenesis, Oxford, UK, provided writing assistance for this publication. Editorial assistance in formatting, proofreading, copy editing, and fact checking was also provided by Oxford PharmaGenesis. Shire International GmBH provided funding to Oxford PharmaGenesis for support in writing and editing this manuscript.

Conflict of Interest

Nicholas Siebers is an employee of Covance Inc. Covance received funding from Shire (Lexington, MA, USA) to conduct this study. Melissa Palmer, Debra G. Silberg, Lee Jennings, Caleb Bliss, and Patrick T. Martin are employees of Shire and own stock or stock options.

Ethical Approval

All procedures in this study were performed in accordance with the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use Guideline for Good Clinical Practice, the 1964 Declaration of Helsinki and its later amendments, and other applicable local ethical and legal requirements. The study protocol and patient documents were approved by an institutional review board before initiating the study.

Informed Consent

All participants provided written informed consent before any study-related procedures were commenced.

Figures

Fig. 1

Plasma and whole blood concentrations in participants following administration of volixibat. Median values in plasma and whole blood were zero at all time points. Data are from the pharmacokinetic analysis set

Fig. 2

Structure of volixibata. aChemical name: potassium((2R,3R,4S,5R,6R)-4-benzyloxy-6-(3-[3-((3S,4R,5R)-3-butyl-7-dimethylamino-3-ethyl-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-benzo[b] thiepin-5-yl)-phenyl]-ureido)-3,5-dihydroxy-tetrahydro-pyran-2-ylmethyl)sulfate ethanolate, hydrate