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Obeticholic Acid
Indications
Obeticholic acid (OCA) is a synthetic derivative of chenodeoxycholic acid, an endogenous primary bile acid. Obeticholic acid was initially developed to treat liver and bile duct pathologies and has demonstrated efficacy as an anti-cholestatic and antihepatotoxic agent. Obeticholic acid is FDA-approved for treating primary biliary cholangitis (PBC). The use of OCA for primary sclerosing cholangitis (PSC) and nonalcoholic steatohepatitis (NASH) is still under study.[1] Obeticholic acid is a novel therapy and the first FDA-approved semi-synthetic agonist of the farnesoid X receptor (FXR).[2]
FDA-Approved Indications
Primary Biliary Cholangitis
Obeticholic acid has only received FDA approval to treat PBC, a disease characterized by progressive inflammatory destruction of small intrahepatic bile ducts.[3] Obeticholic acid is approved for use in combination with ursodeoxycholic acid (UDCA) for patients who have had an inadequate biochemical response after a year of UDCA monotherapy. Obeticholic acid is FDA-approved for the treatment of adult patients with PBC without cirrhosis or with compensated cirrhosis who do not have evidence of portal hypertension, either in combination with UDCA for those with an inadequate response to UDCA or as monotherapy for patients unable to tolerate UDCA. Obeticholic acid received accelerated approval for this indication based on data demonstrating reduced alkaline phosphatase (ALP) levels. A benefit regarding disease-related symptoms or survival has not been established.[4] A retrospective analysis evaluated the role of OCA in managing PBC, particularly as a second-line therapy after UDCA treatment. Approximately 8% of patients were prescribed OCA due to UDCA intolerance. The study highlights OCA's efficacy in reducing alkaline phosphatase levels in PBC, emphasizing its emerging role as a therapeutic option with greater efficacy than UDCA.[5]
Off-Label Uses
Primary Sclerosing Cholangitis
Primary sclerosing cholangitis is characterized by progressive inflammation, fibrosis, and sclerosis of medium to large-sized bile ducts leading to biliary strictures. There is no known effective medical therapy. A phase 2 trial studying OCA as a treatment for PSC in 77 patients over 24 weeks showed reductions in serum ALP in patients receiving OCA at 5 and 10 mg doses.[6]
Nonalcoholic Steatohepatitis
The FDA does not approve obeticholic acid to treat nonalcoholic fatty liver disease (NAFLD) or NASH; however, its effects on these conditions have been documented. During a multicenter, randomized, controlled phase 3 trial, patients were given a placebo, OCA 10 mg, or OCA 25 mg daily for 18 months to patients in 3 groups: adults with NASH, NAFLD, or signs of fibrosis stages F2-F3 (or F1 with accompanying comorbidity). An interim analysis revealed that OCA 25 mg significantly improved inflammation and fibrosis in patients with NASH.[7] Similarly, another randomized control trial showed that administration of OCA 40 mg/d for 72 weeks in patients with NASH improved the histological features and fibrosis associated with this condition.[8]
A systematic review and meta-analysis evaluated the efficacy of obeticholic acid (OCA) for treating nonalcoholic steatohepatitis (NASH). Five randomized controlled trials were analyzed, focusing on biochemical and histological outcomes in patients with NASH diagnosed by imaging or histology. Obeticholic acid administration significantly reduced liver function marker levels (ie, alanine transaminase and aspartate aminotransferase) and reduced fibrosis and steatosis.[9]
Obeticholic acid has also shown promising results for conditions such as NAFLD with type 2 diabetes and bile acid diarrhea.[10][11]
Mechanism of Action
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Mechanism of Action
Obeticholic acid (OCA) is a semisynthetic hydrophobic bile acid analog that acts as a highly selective agonist for the farnesoid X-activated receptor (FXR), a nuclear bile acid receptor.[2] Farnesoid X-activated receptors are primarily expressed in human enterocytes and hepatocytes. Naturally occurring bile acids are the most common ligands for FXRs. In enterocytes, FXRs regulate the synthesis of bile acids and release a fibroblast growth factor (FGF-19) into the hepatic portal circulation.[12]
FXRs primarily regulate hepatocyte hepatic triglyceride synthesis, fibrosis, and other metabolic pathways. Once FGF-19 is released into the portal circulation, it binds to the FGFR-4 receptor on the hepatocytes. This receptor complex eventually suppresses cholesterol 7α-hydroxylase (CYP7A1), the enzyme responsible for converting cholesterol into bile acids.[13]
This primary pathway inhibits bile acid synthesis by the hepatocytes. FXRs in the hepatocytes are also activated by circulating bile acids to stimulate the bile salt export pump (BSEP) to increase bile salt excretion. Upon intake, obeticholic acid is metabolized by the liver into glycine and taurine. Later, these conjugated products are secreted into the bile and absorbed by the small intestine. After glycine and taurine enter enterohepatic circulation, intestinal microbes deconjugate back into OCA.[14]
Obeticholic acid selectively binds and activates the FXRs of enterocytes and hepatocytes, reducing the toxic levels of bile acids. Compared with naturally occurring bile acids, its binding potency is over 100-fold, effectively blunting the harmful effects of bile acids on hepatic tissues. Reducing this exposure limits the progression of cholangitic processes such as PBC and PSC. Obeticholic acid also directly stimulates the BSEP to reduce circulating bile salts in the liver and biliary tree.
While obeticholic acid has not been approved for use in patients with NASH, the data from some studies suggest OCA's efficacy in suppressing hepatic triglyceride synthesis and promoting insulin sensitivity and insulin-dependent activities. This suppression reduces the risk of lipid deposition into hepatocytes, reducing the incidence and progression of NASH.[11]
Pharmacokinetics
Absorption: Obeticholic acid reaches peak plasma concentrations (Tmax) at ~1.5 hours, and the alkaline phosphatase reduction plateau at ~3 months. Food does not alter absorption.
Distribution: Obeticholic acid and its metabolites demonstrate plasma protein binding of >99%. The volume of distribution is 618 L.
Metabolism: Obeticholic acid is conjugated with glycine or taurine in the liver and secreted into bile. These conjugates are absorbed in the small intestine, leading to enterohepatic recirculation. Deconjugation by intestinal microbiota in the ileum and colon converts them back to obeticholic acid, which is reabsorbed or excreted in feces, the principal route of elimination.[15]
Elimination: Approximately 87% of the dose is excreted in feces via biliary secretion. Less than 3% is excreted in urine.
Administration
Available Dosage Forms and Strengths
Obeticholic acid is available as a 5 or 10-mg oral tablet for patients with PBC with inadequate response or intolerance to UDCA. An inadequate response is defined as an ALP level greater than 1.67 times the upper limit of normal (ULN) or elevated bilirubin greater than twice the ULN after 1 year of UDCA therapy.[16]
Adult Dosing
The recommended initial dose is 5 mg once daily, which can be increased to 10 mg daily if the patient does not have a reduction in ALP and bilirubin within 3 months and tolerates the drug well.[1][17] The effect of varying FDA-approved OCA doses is currently being studied. One double-blind study of patients with PBC with an inadequate response to UDCA demonstrated that OCA doses ranging from 10 to 50 mg daily for 3 months significantly reduced ALP, γ-glutamyl transpeptidase (GGT) and alanine aminotransferase (ALT) levels.[18] Similarly, another study demonstrated significant improvement in ALP and other biochemical marker levels with OCA 10-50 mg monotherapy.[19] Pruritus as an adverse effect increased in a dose-dependent manner, and the 10 mg dosage demonstrated superior tolerability and fewer discontinuations.[19]
Specific Patient Populations
Hepatic impairment: Obeticholic acid is contraindicated for patients with decompensated cirrhosis (eg, Child-Pugh Class B or C), with a prior history of decompensation events, or with compensated cirrhosis and portal hypertension.
Renal impairment: According to product labeling, any increase in the area under the curve (AUC) of total obeticholic acid in subjects with renal impairment is not clinically significant. Additionally, animal models have demonstrated the beneficial effects of obeticholic acid in the kidney by reducing TNF-α-mediated expression of matrix metalloproteinases (MMPs) after liver ischemia-reperfusion.[20]
Pregnancy considerations: According to the American Association for the Study of Liver Diseases (AASLD), obeticholic acid is not associated with teratogenicity or postnatal abnormalities in animal studies; however, human data are lacking. Due to the insufficient safety data, administration of obeticholic acid during pregnancy is not recommended.
Breastfeeding considerations: Per the AASLD, obeticholic acid's presence in breast milk has not been determined. Due to insufficient safety data, obeticholic acid is not recommended for patients who are breastfeeding.[21]
Pediatric patients: Obeticholic acid has not been established as safe and effective for pediatric patients.
Older patients: No age-related differences in the safety or effectiveness of obeticholic acid have been observed.
Adverse Effects
The most common adverse effects associated with obeticholic acid administration include pruritus, fatigue, and abdominal pain and discomfort. Other reported adverse effects include rash, oropharyngeal pain, dizziness, constipation, arthralgia, dyslipidemia, headache, eczema, depression, hypersensitivity reactions, and abnormal thyroid function.[1][17] The incidence of pruritus has been shown to increase in a dose-dependent manner and is increased when OCA is used as monotherapy. However, if a patient undergoes OCA therapy for 3 months without pruritus, this adverse effect is unlikely to occur subsequently.[22][23][24]
If pruritus does occur, it can be managed with bile acid sequestrants, antihistamines, dose reduction, or a temporary dosing interruption.[22] Esophageal varices and ascites were also shown to occur during a 3-year interim analysis of patients in the POISE trial.[25]
Obeticholic acid is also associated with decreases in high-density lipoprotein cholesterol and triglycerides and increases in low-density lipoprotein cholesterol.[16][26][27][28] However, a double-blind, placebo-controlled study of patients with NASH showed that atorvastatin could be in combination with OCA to mitigate LDL changes.[29]
In patients with decompensated cirrhosis or Child-Pugh B or C hepatic impairment who receive more frequent dosing than the recommended starting dosage of 5 mg once weekly, hepatic decompensation and failure have been reported. Patients at risk for hepatic decompensation should be closely monitored while on OCA.
Dose-dependent liver-related adverse reactions such as jaundice, worsening ascites, portal hypertension, and primary biliary cholangitis flare were also reported in patients with doses of 10 to 50 mg (5 times the recommended dose.) A pooled analysis of 3 placebo-controlled trials involving patients with PBC revealed that liver-related adverse effects occurred at a rate of 5.2 per 100 patient exposure years (PEY) for the 10 mg dose versus 2.4 for the placebo group. Liver-related adverse effects were 19.8 per 100 PEY for the 25 mg group and 54.5 per 100 PEY for the 50 mg group.[1] Monitoring the patient's liver function during OCA therapy and liver-related adverse reactions is vital.
Patients who experience paradoxical worsening of liver disease, progressive elevation of liver enzymes, or evidence of hepatic decompensation should discontinue OCA.[1] Patients with cirrhosis presenting with portal hypertension should also discontinue OCA.[30]
Drug-Drug Interactions
Bile acid binding resins (eg, cholestyramine, colestipol, colesevelam): Obeticholic acid absorption and effectiveness may be reduced if administered concurrently with bile acid binding resins. To minimize interaction, obeticholic acid should be taken at least 4 hours before or after these resins.
Warfarin: Coadministration of obeticholic acid with warfarin can lower the International Normalized Ratio (INR). Monitoring INR levels and adjusting warfarin dosage may be necessary to maintain therapeutic efficacy.
Inhibitors of bile salt efflux pump (BSEP) (eg, cyclosporine): Concomitant administration of obeticholic acid with BSEP inhibitors may lead to bile salt accumulation in the liver, potentially causing clinical symptoms. These combinations should be avoided. However, if BSEP inhibitors are necessary, serum transaminase and bilirubin levels should be monitored.
CYP1A2 substrate: Obeticholic acid can potentially increase the exposure of CYP1A2 substrates. Serum drug concentrations should be observed in CYP1A2 substrates with narrow therapeutic indexes, such as theophylline and tizanidine.[17][24]
Contraindications
Obeticholic acid is contraindicated for patients with complete biliary obstruction. Obeticholic acid is also contraindicated for patients with decompensated cirrhosis (eg, Child-Pugh Class B or C) or compensated cirrhosis with evidence of portal hypertension, such as gastroesophageal varices, ascites, or ongoing thrombocytopenia.
Box Warnings
Hepatic decompensation and hepatic failure in primary biliary cholangitis with cirrhosis: The Food and Drug Administration (FDA) has issued a boxed warning stating that administration of obeticholic acid to patients with primary biliary cholangitis (PBC) and compensated or decompensated cirrhosis is associated with hepatic decompensation and hepatic failure. These adverse effects may be fatal or require liver transplantation. The FDA further notes that obeticholic acid is contraindicated for patients with PBC and decompensated cirrhosis, a history of decompensation events, or compensated cirrhosis with evidence of portal hypertension. Furthermore, OBC was found to fatally exacerbate hepatic decompensation and failure in patients with PBC and decompensated cirrhosis when administered at doses higher than normal. Discontinuation of obeticholic acid is advised for patients with clinical or laboratory indications of hepatic decompensation, compensated cirrhosis with portal hypertension, or clinically significant hepatic adverse reactions.[31][32]
Warning and Precautions
Severe pruritus: Obeticholic acid treatment is associated with severe itching (pruritus) that can interfere with daily activities and may require medical intervention. Management strategies include bile acid binding resins, antihistamines, dose adjustments, or temporary cessation of obeticholic acid.[9]
Reduction in HDL-C: Obeticholic acid treatment is associated with reduced HDL-C levels. These reductions were observed across treatment arms compared to placebo. Monitoring lipid levels is recommended during therapy, particularly for patients experiencing significant and sustained decreases in HDL-C.[33]
Monitoring
The patient's response and tolerability to OBC and progression of PBC disease should be monitored. Also, any relevant Child-Pugh classifications should be updated regularly, as dosage adjustments are based on classification changes. Monitoring liver function, including serum bilirubin, ALT, AST, and alkaline phosphatase, can be performed to assess safety and efficacy.[1]
If the patient has a biliary obstruction, evidence of worsening hepatic function indicating risk of decompensation, or liver-related adverse reactions (such as jaundice, worsening ascites, or PBC flare), OCA should be discontinued. Obeticholic acid is associated with reduced high-density lipoprotein (HDL) and increased low-density lipoprotein (LDL) levels. Serum lipid levels should be monitored during treatment. International Normalized Ratio (INR) should be monitored for necessary dosage adjustments as OCA is associated with reduced INR in patients receiving warfarin.[17]
Toxicity
Signs and Symptoms of Overdose
For patients with primary biliary cholangitis, the administration of obeticholic acid at doses higher than the recommended maximum (ie, 25 mg or 50 mg once daily) results in dose-dependent hepatotoxicity, evidenced by elevations in ascites, portal hypertension, jaundice, and exacerbation of primary biliary cholangitis.
Management of Overdose
There is no antidote for obeticholic acid. The FDA recommends closely monitoring the patient and providing appropriate care during an overdose.
Recommendations
Obeticholic acid should be administered only to patients who have an inadequate response or are intolerant to UDCA alone.[5]
Enhancing Healthcare Team Outcomes
Obeticholic acid is a relatively new pharmacologic agent used for patients with conditions that have few available treatments. Educating clinicians, administrators, patients, and other healthcare professionals regarding its use and indications is critical. The lack of long-term trials and data also highlights the need for continuing medical education of professionals and patients alike, as new data regarding long-term treatment outcomes and adverse events may arise. Therefore, proper physician practice with differing dosages, patient monitoring, and treatment discontinuation is necessary. Patient comorbidities such as simultaneous renal failure, progressive liver fibrosis leading to cirrhosis, and biliary ductal obstruction must be monitored.
Current FDA guidelines approve OCA for treating PBC in patients who have failed first-line treatment or cannot tolerate UDCA. The FDA recommends routinely monitoring patients on OCA for PBC disease progression with laboratory and clinical assessments to determine whether dosage adjustment is needed. Close monitoring is also recommended for patients at increased risk of hepatic decompensation, including patients with worsening liver function and coagulation. Providers must use their discretion when prescribing OCA and closely monitor and share outcomes with their patients to make an informed team decision regarding dose adjustments and continuing the medication if adverse events occur and after they resolve.
Clinical trials studying the efficacy of OCA for patients with PBC, PSC, NAFLD, NASH, and type 2 diabetes have all shown promising results. The results of these studies suggest that OCA, as a monotherapy or in conjunction with conventional therapy, may effectively treat these diseases. More studies are required on the efficacy of OCA against various other hepatic and pancreatic-related conditions. The POISE trial showed that OCA treatment significantly improved transplant-free survival in patients with PBC compared to the control group.[34] The primary care physician should coordinate with the gastroenterologist and hepatologist for optimal use of OCA. The pharmacist should verify dosing, check for potential interactions, and report any discrepancies to the prescriber. An interprofessional team approach and communication among clinicians (MDs, DOs, NPs, PAs), hepatologists, pharmacists, and nurses are crucial to reducing adverse effects and enhancing patient outcomes associated with obeticholic acid.
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