دورية أكاديمية
أعرض في EDS

A randomised, double-blind, placebo-controlled phase 1 study of the safety, tolerability and pharmacodynamics of volixibat in overweight and obese but otherwise healthy adults: implications for treatment of non-alcoholic steatohepatitis.

التفاصيل البيبلوغرافية
العنوان: A randomised, double-blind, placebo-controlled phase 1 study of the safety, tolerability and pharmacodynamics of volixibat in overweight and obese but otherwise healthy adults: implications for treatment of non-alcoholic steatohepatitis.
المؤلفون: Palmer M; Global Development Lead Hepatology, Shire, 300 Shire Way, Lexington, MA, 02421, USA. mpalmer@shire.com., Jennings L; Global Development Lead Hepatology, Shire, 300 Shire Way, Lexington, MA, 02421, USA., Silberg DG; Shire International GmbH, Zahlerweg 10, 6301, Zug, Switzerland., Bliss C; Global Development Lead Hepatology, Shire, 300 Shire Way, Lexington, MA, 02421, USA., Martin P; Global Development Lead Hepatology, Shire, 300 Shire Way, Lexington, MA, 02421, USA.
المصدر: BMC pharmacology & toxicology [BMC Pharmacol Toxicol] 2018 Mar 16; Vol. 19 (1), pp. 10. Date of Electronic Publication: 2018 Mar 16.
نوع المنشور: Clinical Trial, Phase I; Journal Article; Randomized Controlled Trial; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: BioMed Central Country of Publication: England NLM ID: 101590449 Publication Model: Electronic Cited Medium: Internet ISSN: 2050-6511 (Electronic) Linking ISSN: 20506511 NLM ISO Abbreviation: BMC Pharmacol Toxicol Subsets: MEDLINE
أسماء مطبوعة: Original Publication: London : BioMed Central
مواضيع طبية MeSH: Benzothiepins/*administration & dosage , Glycosides/*administration & dosage , Lipid Regulating Agents/*administration & dosage , Overweight/*metabolism, Adult ; Benzothiepins/adverse effects ; Benzothiepins/pharmacokinetics ; Bile Acids and Salts/analysis ; Cholestenones/blood ; Double-Blind Method ; Feces/chemistry ; Female ; Glycosides/adverse effects ; Glycosides/pharmacokinetics ; Healthy Volunteers ; Humans ; Lipid Regulating Agents/adverse effects ; Lipid Regulating Agents/pharmacokinetics ; Lipids/blood ; Male ; Middle Aged
مستخلص: Background: Accumulation of toxic free cholesterol in hepatocytes may cause hepatic inflammation and fibrosis. Volixibat inhibits bile acid reuptake via the apical sodium bile acid transporter located on the luminal surface of the ileum. The resulting increase in bile acid synthesis from cholesterol could be beneficial in patients with non-alcoholic steatohepatitis. This adaptive dose-finding study investigated the safety, tolerability, pharmacodynamics, and pharmacokinetics of volixibat.
Methods: Overweight and obese adults were randomised 3:1 to double-blind volixibat or placebo, respectively, for 12 days. Volixibat was initiated at a once-daily dose of 20 mg, 40 mg or 80 mg. Based on the assessment of predefined safety events, volixibat dosing was either escalated or reduced. Other dose regimens (titrations and twice-daily dosing) were also evaluated. Assessments included safety, tolerability, stool hardness, faecal bile acid (FBA) excretion, and serum levels of 7α-hydroxy-4-cholesten-3-one (C4) and lipids.
Results: All 84 randomised participants (volixibat, 63; placebo, 21) completed the study, with no serious adverse events at doses of up to 80 mg per day (maximum assessed dose). The median number of daily bowel evacuations increased from 1 (range 0-4) to 2 (0-8) during volixibat treatment, and stool was looser with volixibat than placebo. Volixibat was minimally absorbed; serum levels were rarely quantifiable at any dose or sampling time point, thereby precluding pharmacokinetic analyses. Mean daily FBA excretion was 930.61 μmol (standard deviation [SD] 468.965) with volixibat and 224.75 μmol (195.403) with placebo; effects were maximal at volixibat doses ≥20 mg/day. Mean serum C4 concentrations at day 12 were 98.767 ng/mL (standard deviation, 61.5841) with volixibat and 16.497 ng/mL (12.9150) with placebo. Total and low-density lipoprotein cholesterol levels decreased in the volixibat group, with median changes of - 0.70 mmol/L (range - 2.8 to 0.4) and - 0.6990 mmol/L (- 3.341 to 0.570), respectively.
Conclusions: This study indicates that maximal inhibition of bile acid reabsorption, as assessed by FBA excretion, occurs at volixibat doses of ≥20 mg/day in obese and overweight adults, without appreciable change in gastrointestinal tolerability. These findings guided dose selection for an ongoing phase 2 study in patients with non-alcoholic steatohepatitis.
Trial Registration: ClinicalTrials.gov identifier: NCT02287779 (registration first received 6 November 2014).
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فهرسة مساهمة: Keywords: Apical sodium-dependent bile acid transporter (ASBT); Cholesterol; LUM002; Non-alcoholic fatty liver disease; Non-alcoholic steatohepatitis; Obesity; SHP626; Volixibat
سلسلة جزيئية: ClinicalTrials.gov NCT02287779
المشرفين على المادة: 0 (Benzothiepins)
0 (Bile Acids and Salts)
0 (Cholestenones)
0 (Glycosides)
0 (Lipid Regulating Agents)
0 (Lipids)
3862-25-7 (7 alpha-hydroxy-4-cholesten-3-one)
X2JZ0451H8 (volixibat)
تواريخ الأحداث: Date Created: 20180318 Date Completed: 20190326 Latest Revision: 20190326
رمز التحديث: 20231215
مُعرف محوري في PubMed: PMC5857122
DOI: 10.1186/s40360-018-0200-y
PMID: 29548345
قاعدة البيانات: MEDLINE
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