Shukla Ajay Kumar, Misra Saurav
Department of Pharmacology, AIIMS Bhopal, Bhopal, Madhya Pradesh, India.
Department of Pharmacology, Kalpana Chawla Government Medical College, Karnal, Haryana, India.
J Basic Clin Physiol Pharmacol. 2025 Aug 11. doi: 10.1515/jbcpp-2024-0124.
Primary biliary cholangitis (PBC) is a chronic liver disease leading to liver damage and potentially death. The first-line treatment is ursodeoxycholic acid (UDCA), but some patients do not respond well. Obeticholic acid (OCA) is a second-line treatment option. Fenofibrate (a predominantly PPAR-α agonist) and bezafibrate (a pan-PPAR agonist) are currently used in clinical practice as anticholestatic agents to improve serum biochemistry in PBC. Seladelpar, a peroxisome proliferator-activated receptor-delta (PPARδ) agonist, has demonstrated potent anti-cholestatic effects in clinical studies. The aim of this analysis was to summarise the data available on efficacy and safety of seladelpar for the treatment of primary biliary cholangitis (PBC). We conducted a search in PubMed, Embase and Web of Science for studies on seladelpar until June 1, 2024. The analysis included review articles, randomized controlled trials, cohort studies and case-control studies. Seladelpar is a once daily oral, potent and selective PPAR-δ agonist. Activation of PPAR-δ on hepatocytes and cholangiocytes improves cholestasis by downregulating the rate-limiting enzyme, CYP 7A1, used for bile synthesis, as well as reducing cholesterol synthesis and dietary absorption, leading to a reduction in bile acid pools. In this review, we have summarised the preclinical and clinical data on seladelpar. There is a need for additional phase III studies to provide sufficient clinical evidence for the efficacy and safety of this investigational drug, as current evidence is limited to phase III studies and does not yet prove its worth in a larger population.
原发性胆汁性胆管炎（PBC）是一种导致肝脏损伤甚至可能危及生命的慢性肝病。一线治疗药物是熊去氧胆酸（UDCA），但部分患者对此反应不佳。奥贝胆酸（OCA）是二线治疗选择。非诺贝特（一种主要的PPAR-α激动剂）和苯扎贝特（一种泛PPAR激动剂）目前在临床实践中用作抗胆汁淤积药物，以改善PBC患者的血清生化指标。司美格鲁肽，一种过氧化物酶体增殖物激活受体-δ（PPARδ）激动剂，在临床研究中已显示出强大的抗胆汁淤积作用。本分析的目的是总结司美格鲁肽治疗原发性胆汁性胆管炎（PBC）的有效性和安全性的现有数据。我们在PubMed、Embase和Web of Science上检索了截至2024年6月1日的关于司美格鲁肽的研究。该分析包括综述文章、随机对照试验、队列研究和病例对照研究。司美格鲁肽是一种每日口服一次的强效选择性PPAR-δ激动剂。肝细胞和胆管细胞上PPAR-δ的激活通过下调用于胆汁合成的限速酶CYP 7A1，以及减少胆固醇合成和饮食吸收，从而改善胆汁淤积，导致胆汁酸池减少。在本综述中，我们总结了司美格鲁肽的临床前和临床数据。由于目前的证据仅限于III期研究，尚未在更大规模人群中证明其价值，因此需要进行更多的III期研究，为这种研究性药物的有效性和安全性提供充分的临床证据。
