Evolving therapeutic landscape of primary biliary cholangitis: A review

Table 1 Pharmacologic agents for primary biliary cholangitis: Mechanisms, clinical effects, contraindications, and notable adverse effects

Drug	Typical dose	Mechanism of action	Key clinical effects	Contraindications/major cautions	Notable adverse effects
Obeticholic acid	5-10 mg once daily (dose adjustments may be required in cirrhosis)	Farnesoid X receptor agonist; decreases bile acid synthesis and promotes bile flow	Improves ALP and other liver enzymes; May reduce fibrosis progression; Used if inadequate response or intolerance to UDCA	Decompensated cirrhosis (Child-Pugh B or C) without appropriate dose adjustment may precipitate hepatic decompensation; Complete biliary obstruction Exercise caution in severe renal impairment	Pruritus (often significant); Fatigue; Hepatic decompensation in advanced cirrhosis; May decrease HDL cholesterol
Bezafibrate	400 mg/day	Primarily a peroxisome proliferator–activated receptor alpha (PPAR-α) agonist (with some activity on PPAR-δ/γ); reduces triglycerides and may enhance bile acid transporter function	Improves LFTs; May alleviate pruritus in certain patients; Enhances GLOBE and UK-PBC scores when added to UDCA	Significant renal impairment: Fibrates generally require dose adjustment or avoidance; Possible impact on gallbladder disease risk (due to changes in biliary lipid composition); Monitor for interactions with statins (risk of myopathy)	Elevated creatinine or creatine kinase levels (myopathy risk, especially with concomitant statin therapy); Gastrointestinal disturbances; Possible gallstone formation
Fenofibrate	100-200 mg/day	PPAR-α agonist; reduces triglyceride, hepatic inflammation and cholestasis	Lowers ALP, GGT, AST, ALT, bilirubin; Potentially decreases disease progression in UDCA nonresponders; May offer survival benefits when used in combination with UDCA	Severe renal impairment requires dose adjustment or avoidance; Active liver disease outside the context of PBC may be exacerbated; Concomitant statin therapy increases risk of myopathy/rhabdomyolysis (use caution)	Gastrointestinal upset; Possible myopathy (especially when combined with statins); Transient elevations in liver enzymes
Seladelpar	2-10 mg once daily	PPAR-δ agonist; modulates bile acid metabolism and inflammation, potentially reduces IL-31 Levels (thereby alleviating pruritus)	Substantial reduction in ALP, transaminases, and bilirubin; Demonstrated efficacy in improving pruritus; Favorable safety profile in multiple Phase II/III clinical trials	Not yet widely approved in all jurisdictions; Use with caution in advanced cirrhosis until further data are available	Generally well tolerated; Transient aminotransferase elevations reported at higher doses in early studies; Few drug–drug interactions reported to date
Elafibranor	80 mg once daily	Dual PPAR-α/δ agonist; reduces ALP, mitigates inflammation, and may beneficially influence lipid metabolism	Lowers ALP, GGT, CRP, IgM; May reduce progression in UDCA-insufficient responders; Potential improvement in pruritus	Decompensated cirrhosis (contraindicated); Use caution in hepatic impairment; Monitor for potential drug–drug interactions (especially those affecting lipid pathways)	Mild gastrointestinal symptoms (most common); Transient CPK elevations; Rare interactions with statins; Generally well tolerated in clinical trials
Linerixibat	Investigational doses: 20-180 mg once daily; 40-90 mg twice daily	Apical Sodium-Dependent Bile Acid Transporter inhibitor; disrupts enterohepatic circulation of bile acids to alleviate pruritus	May reduce pruritus severity in moderate-to-severe cases; Decreases total serum bile acids and fibroblast growth factor 19 (FGF-19), increases 7α-hydroxy-4-cholesten-3-one (C4); Potential improvement in sleep quality if pruritus improves	Investigational; no formal contraindications established yet; Higher doses often cause gastrointestinal adverse events; Caution in patients with chronic diarrhea or malabsorption	Diarrhea (up to approximately 38%–68% with higher doses); Abdominal pain; Study discontinuations often due to gastrointestinal intolerance at higher doses
Setanaxib	400 mg once or twice daily (investigational)	Selective NOX 1/4 inhibitor; attenuates NADPH oxidase–mediated reactive oxygen species (ROS) generation, potentially reversing cholestatic fibrosis and inflammation	May reduce GGT and ALP; May improve fatigue (PBC-40 scores); Anti-fibrotic potential	Investigational; limited data regarding formal contraindications; Should be used with caution in advanced cirrhosis	Gastrointestinal disturbances; Further safety and efficacy data pending

ALT: Alanine aminotransferase; ALP: Alkaline phosphatase; AST: Aspartate transferase; CRP: C-reactive protein; CPK: Creatine phosphokinase; GGT: Gamma-glutamyl transferase; HDL: High-density lipoprotein; IgM: Immunoglobulin M; IL-31: Interleukin 31; LFT: Liver function test; NADPH: Nicotinamide adenine dinucleotide phosphate; NOX: Nicotinamide adenine dinucleotide phosphate oxidase; PPAR-α: Peroxisome proliferator-activated receptor alpha; PPAR-δ: Peroxisome proliferator-activated receptor delta; PPAR-γ: Peroxisome proliferator-activated receptor gamma; PBC: Primary biliary cholangitis; UDCA: Ursodeoxycholic acid.