دورية أكاديمية
أعرض في EDS

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.

التفاصيل البيبلوغرافية
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: Tiessen RG; Early Development Services, Pharmaceutical Research Associates (PRA) Health Sciences, Van Swietenlaan 6, 9728 NZ Groningen, PO Box 8144, 9702, Groningen, KC, Netherlands. tiessenrenger@prahs.com., Kennedy CA; Lumena Pharmaceuticals Inc. (part of the Shire group of companies), 12531 High Bluff Drive, Suite 110, San Diego, CA, 92130, USA., Keller BT; Lumena Pharmaceuticals Inc. (part of the Shire group of companies), 12531 High Bluff Drive, Suite 110, San Diego, CA, 92130, USA., Levin N; Lumena Pharmaceuticals Inc. (part of the Shire group of companies), 12531 High Bluff Drive, Suite 110, San Diego, CA, 92130, USA., Acevedo L; Lumena Pharmaceuticals Inc. (part of the Shire group of companies), 12531 High Bluff Drive, Suite 110, San Diego, CA, 92130, USA., Gedulin B; Lumena Pharmaceuticals Inc. (part of the Shire group of companies), 12531 High Bluff Drive, Suite 110, San Diego, CA, 92130, USA., van Vliet AA; Early Development Services, Pharmaceutical Research Associates (PRA) Health Sciences, Van Swietenlaan 6, 9728 NZ Groningen, PO Box 8144, 9702, Groningen, KC, Netherlands., Dorenbaum A; Lumena Pharmaceuticals Inc. (part of the Shire group of companies), 12531 High Bluff Drive, Suite 110, San Diego, CA, 92130, USA., Palmer M; Lexington, USA.
المصدر: BMC gastroenterology [BMC Gastroenterol] 2018 Jan 05; Vol. 18 (1), pp. 3. Date of Electronic Publication: 2018 Jan 05.
نوع المنشور: Clinical Trial, Phase I; Journal Article; Randomized Controlled Trial
اللغة: English
بيانات الدورية: Publisher: BioMed Central Country of Publication: England NLM ID: 100968547 Publication Model: Electronic Cited Medium: Internet ISSN: 1471-230X (Electronic) Linking ISSN: 1471230X NLM ISO Abbreviation: BMC Gastroenterol Subsets: MEDLINE
أسماء مطبوعة: Original Publication: London : BioMed Central, [2001-
مواضيع طبية MeSH: Benzothiepins/*administration & dosage , Benzothiepins/*adverse effects , Diabetes Mellitus, Type 2/*drug therapy , Glycosides/*administration & dosage , Glycosides/*adverse effects , Membrane Glycoproteins/*antagonists & inhibitors , Non-alcoholic Fatty Liver Disease/*drug therapy , Organic Anion Transporters, Sodium-Dependent/*antagonists & inhibitors , Symporters/*antagonists & inhibitors, Adolescent ; Adult ; Aged ; Benzothiepins/pharmacokinetics ; Bile Acids and Salts/analysis ; Bile Acids and Salts/metabolism ; Blood Glucose/metabolism ; Cholestenones/blood ; Diabetes Mellitus, Type 2/metabolism ; Double-Blind Method ; Feces/chemistry ; Female ; Glycosides/pharmacokinetics ; Homeostasis ; Humans ; Lipid Metabolism ; Male ; Middle Aged ; Young Adult
مستخلص: 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).
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معلومات مُعتمدة: Not applicable This study was funded by Lumena Pharmaceuticals (part of the Shire group of companies)
فهرسة مساهمة: Keywords: Apical sodium-dependent bile acid transporter; Bile acids; Clinical pharmacology; LUM002; Non-alcoholic fatty liver disease; Non-alcoholic steatohepatitis; Phase 1 clinical trial; SHP626; Type 2 diabetes mellitus; Volixibat
المشرفين على المادة: 0 (Benzothiepins)
0 (Bile Acids and Salts)
0 (Blood Glucose)
0 (Cholestenones)
0 (Glycosides)
0 (Membrane Glycoproteins)
0 (Organic Anion Transporters, Sodium-Dependent)
0 (Symporters)
145420-23-1 (sodium-bile acid cotransporter)
3862-25-7 (7 alpha-hydroxy-4-cholesten-3-one)
X2JZ0451H8 (volixibat)
تواريخ الأحداث: Date Created: 20180107 Date Completed: 20180730 Latest Revision: 20181113
رمز التحديث: 20240628
مُعرف محوري في PubMed: PMC5756385
DOI: 10.1186/s12876-017-0736-0
PMID: 29304731
قاعدة البيانات: MEDLINE
الوصف
تدمد:1471-230X
DOI:10.1186/s12876-017-0736-0