Safety, tolerability and pharmacodynamics of apical sodium-dependent bile acid transporter inhibition with volixibat in healthy adults and patients with type 2 diabetes mellitus: a randomised placebo-controlled trial

Autor: Andre van Vliet, Bradley T. Keller, Melissa Palmer, Alejandro Dorenbaum, Ciara Kennedy, Renger G. Tiessen, Lisette Acevedo, Bronislava Gedulin, Nancy Levin
Rok vydání: 2017
Předmět:
0301 basic medicine
Blood Glucose
Male
Placebo-controlled study
Benzothiepins
Gastroenterology
LUM002
chemistry.chemical_compound
Feces
0302 clinical medicine
Non-alcoholic Fatty Liver Disease
Homeostasis
Glycosides
SHP626
Non-alcoholic steatohepatitis
Membrane Glycoproteins
Symporters
General Medicine
Middle Aged
Tolerability
030211 gastroenterology & hepatology
Female
Apical sodium-dependent bile acid transporter
Clinical pharmacology
Research Article
Adult
medicine.medical_specialty
Adolescent
Organic Anion Transporters
Sodium-Dependent
Placebo
Bile Acids and Salts
03 medical and health sciences
Young Adult
Pharmacokinetics
Double-Blind Method
Internal medicine
Type 2 diabetes mellitus
medicine
Humans
lcsh:RC799-869
Adverse effect
Cholestenones
Aged
Cholesterol
business.industry
Volixibat
Phase 1 clinical trial
medicine.disease
Lipid Metabolism
Bile acids
030104 developmental biology
chemistry
Diabetes Mellitus
Type 2
Pharmacodynamics
lcsh:Diseases of the digestive system. Gastroenterology
Steatohepatitis
business
Zdroj: BMC Gastroenterology
BMC Gastroenterology, Vol 18, Iss 1, Pp 1-17 (2018)
ISSN: 1471-230X
Popis: Background Pathogenesis in non-alcoholic steatohepatitis (NASH) involves abnormal cholesterol metabolism and hepatic accumulation of toxic free cholesterol. Apical sodium-dependent bile acid transporter (ASBT) inhibition in the terminal ileum may facilitate removal of free cholesterol from the liver by reducing recirculation of bile acids (BAs) to the liver, thereby stimulating new BA synthesis from cholesterol. The aim of this phase 1 study in adult healthy volunteers (HVs) and patients with type 2 diabetes mellitus (T2DM) was to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of ASBT inhibition with volixibat (SHP626; formerly LUM002). Methods Participants were randomised 3:1 to receive once-daily oral volixibat (0.5 mg, 1 mg, 5 mg or 10 mg) or placebo for 28 days in two cohorts (HV and T2DM). Assessments included safety, faecal BA and serum 7α-hydroxy-4-cholesten-3-one (C4; BA synthesis biomarker). Results Sixty-one individuals were randomised (HVs: placebo, n = 12; volixibat, n = 38; T2DM: placebo, n = 3; volixibat, n = 8). No deaths or treatment-related serious adverse events were reported. Mild or moderate gastrointestinal adverse events were those most frequently reported with volixibat. With volixibat, mean total faecal BA excretion on day 28 was ~1.6–3.2 times higher in HVs (643.73–1239.3 μmol/24 h) and ~8 times higher in T2DM (1786.0 μmol/24 h) than with placebo (HVs: 386.93 μmol/24 h; T2DM: 220.00 μmol/24 h). With volixibat, mean C4 concentrations increased by ~1.3–5.3-fold from baseline to day 28 in HVs and by twofold in T2DM. Conclusions Volixibat was generally well tolerated. Increased faecal BA excretion and serum C4 levels support the mechanistic rationale for exploring ASBT inhibition in NASH. The study was registered with the Dutch clinical trial authority (Centrale Commissie Mensgebonden Onderzoek; trial registration number NL44732.056.13; registered 24 May 2013). Electronic supplementary material The online version of this article (10.1186/s12876-017-0736-0) contains supplementary material, which is available to authorized users.
Databáze: OpenAIRE
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