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
| 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 |
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| المؤلفون: | Lee Jennings, Caleb Bliss, Debra G. Silberg, Patrick Martin, Melissa Palmer |
| المصدر: | BMC Pharmacology and Toxicology, Vol 19, Iss 1, Pp 1-13 (2018) BMC Pharmacology & Toxicology |
| بيانات النشر: | Springer Science and Business Media LLC, 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | Male, 0301 basic medicine, Benzothiepins, Gastroenterology, LUM002, Feces, chemistry.chemical_compound, 0302 clinical medicine, Pharmacology (medical), Glycosides, SHP626, Non-alcoholic steatohepatitis, Bile acid, Middle Aged, Lipids, Healthy Volunteers, Cholesterol, Tolerability, Female, 030211 gastroenterology & hepatology, Research Article, Adult, medicine.medical_specialty, medicine.drug_class, Placebo, Apical sodium-dependent bile acid transporter (ASBT), Bile Acids and Salts, Excretion, 03 medical and health sciences, Double-Blind Method, Pharmacokinetics, lcsh:RA1190-1270, Internal medicine, medicine, Humans, Obesity, Cholestenones, lcsh:Toxicology. Poisons, Pharmacology, Lipid Regulating Agents, business.industry, lcsh:RM1-950, Volixibat, Overweight, medicine.disease, lcsh:Therapeutics. Pharmacology, 030104 developmental biology, chemistry, Pharmacodynamics, Steatohepatitis, business, Non-alcoholic fatty liver disease |
| الوصف: | 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). Electronic supplementary material The online version of this article (10.1186/s40360-018-0200-y) contains supplementary material, which is available to authorized users. |
| تدمد: | 2050-6511 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::abb9c6392205eaffe3f6721efd235f9b https://doi.org/10.1186/s40360-018-0200-y |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....abb9c6392205eaffe3f6721efd235f9b |
| قاعدة البيانات: | OpenAIRE |
Find this article in full text from Springer Verlag. | تدمد: | 20506511 |
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