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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

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العنوان: 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
المؤلفون: Andre van Vliet, Bradley T. Keller, Melissa Palmer, Alejandro Dorenbaum, Ciara Kennedy, Renger G. Tiessen, Lisette Acevedo, Bronislava Gedulin, Nancy Levin
المصدر: BMC Gastroenterology
BMC Gastroenterology, Vol 18, Iss 1, Pp 1-17 (2018)
سنة النشر: 2017
مصطلحات موضوعية: 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
الوصف: 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.
تدمد: 1471-230X
URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::bccbc1bd1d43bb9965c0709ba31ffdf0
https://pubmed.ncbi.nlm.nih.gov/29304731
حقوق: OPEN
رقم الأكسشن: edsair.doi.dedup.....bccbc1bd1d43bb9965c0709ba31ffdf0
قاعدة البيانات: OpenAIRE
الوصف
تدمد:1471230X