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      Bioequivalence and Pharmacokinetic Profiles of Generic and Branded Obeticholic Acid in Healthy Chinese Subjects Under Fasting and Fed Conditions

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          This study was conducted to evaluate the bioequivalence (BE) of a generic form of obeticholic acid (OCA) and Ocaliva TM under fasting and fed conditions and to determine the effects of food on the pharmacokinetic (PK) profiles of OCA in healthy Chinese subjects.


          A randomized, single-dose, three-sequence, three-period, partial replicated crossover study was conducted with a 21-day washout interval between periods under fasting (n=48) and fed (n=48) conditions. Blood samples for OCA and its metabolites Glyco-OCA and Tauro-OCA were collected up to 168 hours after administration in each period. PK parameters were calculated using the non-compartmental method. Geometric mean ratios for PK parameters of the test to reference drug under fasting and fed conditions and their 90% confidence intervals were estimated. Safety evaluations were carried out all through the study.


          A total of 91 subjects completed the study with 45 in a fasted state and 46 receiving a high-fat diet. There were no serious or unexpected drug-related adverse events occurring during the study. There was no significant difference in the main PK parameters of the two preparations, irrespective of the fasting or fed conditions. Under fasting and fed conditions, the S WR of lnC max, lnAUC 0-t and lnAUC 0-∞ were 0.445, 0.370, 0.448, 0.340, 0.168, and 0.180, respectively. Thus, the average BE or the reference-scaled average BE was used to verify that the two preparations were bioequivalent under fasting and fed conditions. Compared with the fasting state, the AUC 0-t of the test drug, the AUC 0-t, and AUC 0-∞ of the reference drug were higher in the fed state.


          The test drug and the reference drug were BE and well tolerated in Chinese healthy subjects under both fasting and fed conditions. Food-intake may cause a significant difference in the main PK parameters of the two preparations.

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          Most cited references 18

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          Bile acid receptors as targets for drug development.

          The intracellular nuclear receptor farnesoid X receptor and the transmembrane G protein-coupled receptor TGR5 respond to bile acids by activating transcriptional networks and/or signalling cascades. These cascades affect the expression of a great number of target genes relevant for bile acid, cholesterol, lipid and carbohydrate metabolism, as well as genes involved in inflammation, fibrosis and carcinogenesis. Pregnane X receptor, vitamin D receptor and constitutive androstane receptor are additional nuclear receptors that respond to bile acids, albeit to a more restricted set of species of bile acids. Recognition of dedicated bile acid receptors prompted the development of semi-synthetic bile acid analogues and nonsteroidal compounds that target these receptors. These agents hold promise to become a new class of drugs for the treatment of chronic liver disease, hepatocellular cancer and extrahepatic inflammatory and metabolic diseases. This Review discusses the relevant bile acid receptors, the new drugs that target bile acid signalling and their possible applications.
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            Primary biliary cirrhosis.

            Primary biliary cirrhosis is a chronic cholestatic liver disease characterised by destruction of small intrahepatic bile ducts, leading to fibrosis and potential cirrhosis through resulting complications. The serological hallmark of primary biliary cirrhosis is the antimitochondrial antibody, a highly disease-specific antibody identified in about 95% of patients with primary biliary cirrhosis. These patients usually have fatigue and pruritus, both of which occur independently of disease severity. The typical course of primary biliary cirrhosis has changed substantially with the introduöction of ursodeoxycholic acid (UDCA). Several randomised placebo-controlled studies have shown that UDCA improves transplant-free survival in primary biliary cirrhosis. However, about 40% of patients do not have a biochemical response to UDCA and would benefit from new therapies. Liver transplantation is a life-saving surgery with excellent outcomes for those with decompensated cirrhosis. Meanwhile, research on nuclear receptor hormones has led to the development of exciting new potential treatments. This Seminar will review the current understanding of the epidemiology, pathogenesis, and natural history of primary biliary cirrhosis, discuss management of the disease and its sequelae, and introduce research on new therapeutic options.
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              Intestine farnesoid X receptor agonist and the gut microbiota activate G-protein bile acid receptor-1 signaling to improve metabolism.

              Bile acids activate farnesoid X receptor (FXR) and G protein-coupled bile acid receptor-1 (aka Takeda G protein-coupled receptor-5 [TGR5]) to regulate bile acid metabolism and glucose and insulin sensitivity. FXR and TGR5 are coexpressed in the enteroendocrine L cells, but their roles in integrated regulation of metabolism are not completely understood. We reported recently that activation of FXR induces TGR5 to stimulate glucagon-like peptide-1 (GLP-1) secretion to improve insulin sensitivity and hepatic metabolism. In this study, we used the intestine-restricted FXR agonist fexaramine (FEX) to study the effect of activation of intestinal FXR on the gut microbiome, bile acid metabolism, and FXR and TGR5 signaling. The current study revealed that FEX markedly increased taurolithocholic acid, increased secretion of fibroblast growth factors 15 and 21 and GLP-1, improved insulin and glucose tolerance, and promoted white adipose tissue browning in mice. Analysis of 16S ribosomal RNA sequences of the gut microbiome identified the FEX-induced and lithocholic acid-producing bacteria Acetatifactor and Bacteroides. Antibiotic treatment completely reversed the FEX-induced metabolic phenotypes and inhibited taurolithocholic acid synthesis, adipose tissue browning, and liver bile acid synthesis gene expression but further increased intestinal FXR target gene expression. FEX treatment effectively improved lipid profiles, increased GLP-1 secretion, improved glucose and insulin tolerance, and promoted adipose tissue browning, while antibiotic treatment reversed the beneficial metabolic effects of FEX in obese and diabetic mice.

                Author and article information

                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                14 January 2021
                : 15
                : 185-193
                [1 ]Center for Clinical Pharmacology, The Third Xiangya Hospital, Central South University , Changsha, Hunan 410013, People’s Republic of China
                [2 ]Research and Development Center, Nanjing Chia Tai Tianqing Pharmaceutical Co., Ltd ., Nanjing 210038, People’s Republic of China
                [3 ]Research Center of Drug Clinical Evaluation of Central South University , Changsha, Hunan 410013, People’s Republic of China
                [4 ]XiangYa School of Pharmaceutical Sciences, Central South University , Changsha, Hunan 410013, People’s Republic of China
                [5 ]National-Local Joint Engineering Laboratory of Drug Clinical Evaluation Technology , Changsha, Hunan 410013, People’s Republic of China
                [6 ]Department of Pharmacy, The Third Xiangya Hospital, Central South University , Changsha, Hunan 410013, People’s Republic of China
                Author notes
                Correspondence: Jie Huang; Qi Pei The Third Xiangya Hospital, Central South University , Yinpenling Street, Yuelu District, Changsha, Hunan410013, People’s Republic of ChinaTel +86 15116469024Fax +86 731 8861 8326 Email cellahuang1988@163.com; peiqi1028@126.com

                These authors contributed equally to this work

                © 2021 Wang et al.

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                Page count
                Figures: 2, Tables: 12, References: 20, Pages: 9
                Original Research


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