963
Views
0
CrossRef citations to date
0
Altmetric
Pharmacology

Safety, tolerability, pharmacokinetics and pharmacodynamics of a novel farnesoid X receptor (FXR) agonist-TQA3526 in healthy Chinese volunteers: a double-blind, randomized, placebo-controlled, dose-escalation, food effect phase I study

, , , , , , , , & show all
Article: 2264850 | Received 08 Jun 2023, Accepted 25 Sep 2023, Published online: 10 Dec 2023

References

  • Carino A, Biagioli M, Marchianò S, et al. Ursodeoxycholic acid is a GPBAR1 agonist and resets liver/intestinal FXR signaling in a model of diet-induced dysbiosis and NASH. Biochim Biophys Acta Mol Cell Biol Lipids. 2019;1864(10):1–11. doi: 10.1016/j.bbalip.2019.07.006.
  • Wong RJ, Aguilar M, Cheung R, et al. Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States. Gastroenterology. 2015;148(3):547–555. doi: 10.1053/j.gastro.2014.11.039.
  • Goldberg D, Ditah IC, Saeian K, et al. Changes in the prevalence of hepatitis C virus infection, nonalcoholic steatohepatitis, and alcoholic liver disease among patients with cirrhosis or liver failure on the waitlist for liver transplantation. Gastroenterology. 2017;152(5):1090–1099.e1. doi: 10.1053/j.gastro.2017.01.003.
  • Estes C, Anstee QM, Arias-Loste MT, et al. Modeling NAFLD disease burden in China, France, Germany, Italy, Japan, Spain, United Kingdom, and United States for the period 2016-2030. J Hepatol. 2018;69(4):896–904. doi: 10.1016/j.jhep.2018.05.036.
  • Nagpal SJ, Kabbany MN, Mohamad B, et al. Portal hypertension complications are frequently the first presentation of NAFLD in patients undergoing liver transplantation evaluation. Dig Dis Sci. 2016;61(7):2102–2107. doi: 10.1007/s10620-016-4124-3.
  • Takahashi Y, Fukusato T. Histopathology of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. World J Gastroenterol. 2014;20(42):15539–15548. doi: 10.3748/wjg.v20.i42.15539.
  • European Medicines Agency. Reflection paper on regulatory requirements for the development of medicinal products for chronic non-infections liver disease (PBC, PSC, NASH); [cited 2018 Nov 26]. https://www.ema.europa.eu/documents/scientific-guideline/reflection-paper-regulatory-requirements-development-medicinal-products-chronic-non-infectious-liver_en.pdf
  • Mandrekar P, Szabo G. Signalling pathways in alcohol-induced liver inflammation. J Hepatol. 2009;50(6):1258–1266. doi: 10.1016/j.jhep.2009.03.007.
  • National Institute of Diabetes and Digestive and Kidney Diseases. Symptoms and causes of NAFLD and NASH; 2016 [cited 2018 Oct 12]. https://www.niddk.nih.gov/health-information/liver-disease/nafld-nash/symptoms-causes
  • Corte CD, Ferrari F, Villani A, et al. Epidemiology and natural history of NAFLD. J Med Biochem. 2015;34(1):13–17. doi: 10.2478/jomb-2014-0049.
  • Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology [published correction appears in gastroenterology. 2012 Aug;143(2):503]. Gastroenterology. 2012;142(7):1592–1609. doi: 10.1053/j.gastro.2012.04.001.
  • Watanabe S, Hashimoto E, Ikejima K, et al. Evidence-based clinical practice guidelines for nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Hepatol Res. 2015;45(4):363–377. doi: 10.1111/hepr.12511.
  • European Association for the Study of the Liver (EASL); European Association for the Study of Diabetes (EASD); European Association for the Study of Obesity (EASO). EASL-EASD-EASO clinical practice guidelines for the management of non-alcoholic fatty liver disease. Obes Facts. 2016;9(2):65–90. doi: 10.1159/000443344.
  • Raza S, Rajak S, Upadhyay A, et al. Current treatment paradigms and emerging therapies for NAFLD/NASH. Front Biosci (Landmark Ed). 2021;26(2):206–237. Published 2021 Jan1. doi: 10.2741/4892.
  • Ratziu V. Pharmacological agents for NASH. Nat Rev Gastroenterol Hepatol. 2013;10(11):676–685. doi: 10.1038/nrgastro.2013.193.
  • Lippman SM, Klein EA, Goodman PJ, et al. Effect of selenium and vitamin E on risk of prostate cancer and other cancers: the selenium and vitamin E cancer prevention trial (SELECT). JAMA. 2009;301(1):39–51. doi: 10.1001/jama.2008.864.
  • Schürks M, Glynn RJ, Rist PM, et al. Effects of vitamin E on stroke subtypes: meta-analysis of randomised controlled trials. BMJ. 2010;341:c5702. doi: 10.1136/bmj.c5702.
  • Lincoff AM, Wolski K, Nicholls SJ, et al. Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials. JAMA. 2007;298(10):1180–1188. doi: 10.1001/jama.298.10.1180.
  • Min HK, Kapoor A, Fuchs M, et al. Increased hepatic synthesis and dysregulation of cholesterol metabolism is associated with the severity of nonalcoholic fatty liver disease. Cell Metab. 2012;15(5):665–674. doi: 10.1016/j.cmet.2012.04.004.
  • Younossi ZM, Stepanova M, Nader F, et al. Obeticholic acid impact on quality of life in patients with nonalcoholic steatohepatitis: REGENERATE 18-month interim analysis. Clin Gastroenterol Hepatol. 2022;20(9):2050–2058.e12. doi: 10.1016/j.cgh.2021.07.020.
  • Siddiqui MS, Van Natta ML, Connelly MA, et al. Impact of obeticholic acid on the lipoprotein profile in patients with non-alcoholic steatohepatitis. J Hepatol. 2020;72(1):25–33. doi: 10.1016/j.jhep.2019.10.006.
  • Lammers WJ, van Buuren HR, Hirschfield GM, et al. Levels of alkaline phosphatase and bilirubin are surrogate end points of outcomes of patients with primary biliary cirrhosis: an international follow-up study. Gastroenterology. 2014;147(6):1338–1e15. doi: 10.1053/j.gastro.2014.08.029.
  • Kowdley KV, Luketic V, Chapman R, et al. A randomized trial of obeticholic acid monotherapy in patients with primary biliary cholangitis. Hepatology. 2018;67(5):1890–1902. doi: 10.1002/hep.29569.
  • Holford N. Holford NHG and Sheiner LB “Understanding the dose-effect relationship-clinical application of pharmacokinetic-pharmacodynamic models”, Clin Pharmacokin 6:429–453 (1981)–The Backstory. AAPS J. 2011;13(4):662–664. doi: 10.1208/s12248-011-9306-5.
  • Nevens F, Andreone P, Mazzella G, et al. A placebo-controlled trial of obeticholic acid in primary biliary cholangitis. N Engl J Med. 2016;375(7):631–643. doi: 10.1056/NEJMoa1509840.
  • Alemi F, Kwon E, Poole DP, et al. The TGR5 receptor mediates bile acid-induced itch and analgesia. J Clin Invest. 2013;123(4):1513–1530. doi: 10.1172/JCI64551.
  • Cipriani S, Mencarelli A, Palladino G, et al. FXR activation reverses insulin resistance and lipid abnormalities and protects against liver steatosis in Zucker (fa/fa) obese rats. J Lipid Res. 2010;51(4):771–784. doi: 10.1194/jlr.M001602.
  • Pencek R, Marmon T, Roth JD, et al. Effects of obeticholic acid on lipoprotein metabolism in healthy volunteers. Diabetes Obes Metab. 2016;18(9):936–940. doi: 10.1111/dom.12681.