Continuing Education Activity

Obeticholic acid is a medication used to manage and treat primary biliary cholangitis. This activity describes the indications, action, and contraindications for obeticholic acid as a valuable agent in managing primary biliary cholangitis. This activity will highlight the mechanism of action, adverse event profile, and other key factors of obeticholic acid use pertinent for interprofessional team members in managing patients with primary biliary cholangitis.

Objectives:

• Identify the indications for obeticholic acid.
• Explain the mechanism of action of obeticholic acid.
• Describe the adverse effects of obeticholic acid.
• Review some interprofessional team strategies to improve patient outcomes when using obeticholic acid for biliary pathologies.

Indications

Obeticholic acid (OCA) is a synthetic derivative of the endogenous primary bile acid, chenodeoxycholic acid. Obeticholic acid was developed primarily to treat liver and bile duct pathologies. It has established potency as an anti-cholestatic and antihepatotoxic agent. Currently, OCA has FDA approval for the treatment of primary biliary cholangitis (PBC). The use of OCA for primary sclerosing cholangitis and non-alcoholic steatohepatitis (NASH) is still being researched.[1]

Primary Biliary Cholangitis

As of this writing, obeticholic acid has only received FDA approval to treat PBC, a disease characterized by progressive destruction of small intrahepatic bile ducts by inflammatory cells.[2] Obeticholic acid is approved for use combined with ursodeoxycholic acid (UDCA) for patients who have had an inadequate biochemical response to UDCA monotherapy for ≥ 1 year. Obeticholic acid is also approved as monotherapy for patients with primary biliary cholangitis who cannot tolerate ursodeoxycholic acid. Obeticholic acid was granted accelerated approval by the FDA in 2016 based on reducing alkaline phosphatase (ALP) levels.

Primary Sclerosing Cholangitis

Primary sclerosing cholangitis is a disease of progressive inflammation, fibrosis, and sclerosis of medium to large-sized bile ducts leading to biliary strictures. There is no effective medical therapy. A phase 2 trial studying OCA in PSC in 77 patients over 24 weeks has shown reductions in serum ALP with the OCA treatment at 5 and 10 mg doses.[3] These encouraging studies merit further studies to view the clinical response to treatment. 

Non-alcoholic Steatohepatitis

Obeticholic acid is also not approved by the FDA to treat non-alcoholic fatty liver disease (NAFLD) or NASH; however, its effects on these pathogenic states have been studied previously. In a multicenter, randomized controlled phase 3 trial, placebo, OCA 10 mg, and OCA 25 mg were given daily for 18 months to patients in three groups – adults with NASH, NAFLD, or signs of fibrosis stages F2-F3, or F1 with accompanying comorbidity. This clinical study's interim analysis showed that OCA 25 mg significantly improved fibrosis and histological components of NASH disease among patients with NASH.[4] Similarly, another randomized control trial found that OCA at 40mg/day for 72 weeks against NASH was shown to improve the histological features of NASH and fibrosis.[5] Further follow-up studies will be needed to assess the clinical benefit of OCA in patients with NASH.

Obeticholic acid has also shown promising results in treating other conditions such as NAFLD with Diabetes Mellitus type 2 and bile acid diarrhea.[6][7]

Mechanism of Action

Obeticholic acid is a modified, synthetic bile acid that acts as a farnesoid X-activated receptor (FXR) agonist. Farnesoid X-activated receptors are primarily expressed in human enterocytes and hepatocytes. Naturally occurring bile acids are most often the ligands for FXRs. In the enterocytes, FXRs regulate the synthesis of bile acids and release fibroblast growth factor, specifically FGF-19, into the hepatic portal circulation.[8]

FXRs primarily regulate hepatic triglyceride synthesis, fibrosis, and multiple other metabolic pathways in the hepatocytes. Once FGF-19 is released into the portal circulation, it binds to the FGFR-4 receptor on the hepatocytes. This receptor complex cascades to ultimately lead to the suppression of cholesterol 7 alpha-hydroxylase (CYP7A1), the enzyme responsible for converting cholesterol into bile acids.[9] 

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. Obeticholic acid upon intake is metabolized in the liver and is conjugated into glycine and taurine. Later, the conjugated products are secreted into the bile and absorbed by the small intestine. After these products enter enterohepatic circulation, they are then deconjugated back into OCA by the intestinal microbes.[10]

Obeticholic acid selectively binds and activates the FXRs of the enterocytes and the hepatocytes, thereby reducing the liver and bile ducts to toxic levels of bile acids. Its binding potency, when compared with naturally occurring bile acids, is over 100-fold, effectively blunting the deleterious effects of bile acids on hepatic tissues. Obeticholic acid also directly stimulates the BSEP to decrease circulating bile salts in the liver and biliary tree. By reducing the hepatic exposure to bile acids, the progression of cholangitic processes such as PBC and PSC are limited.

While obeticholic acid has not been approved for use in NASH, current research suggests OCA's activity in suppressing hepatic triglyceride synthesis and promoting insulin sensitivity and insulin-dependent activities decreases the risk of lipid deposition into hepatocytes, reducing the incidence and progression of NASH.[7]

Administration

Obeticholic acid is available as a 5 or 10-milligram oral tablet for patients with PBC with inadequate response or intolerance to UDCA. The inadequate response is defined as ALP greater than 1.67 times the upper limit of normal (ULN) and/or elevated bilirubin greater than two times the ULN after one year of treatment with UDCA.[11] The recommended starting dosage is 5 mg once daily, which can be increased to 10 mg daily if the patient does not have a reduction in ALP and/or bilirubin within three months and tolerates the drug well.[1][12] 

When treating patients with severe liver cirrhosis (Child-Pugh class B or C) or with a prior hepatic decompensation event, the recommendation is to begin with the 5 mg tablet once weekly, and if needed and well-tolerated, it can be increased to 5 mg twice weekly with a minimum of 3 days apart for each dose.[1]

The maximum dose for Child-Pugh Class B or C or patients with a prior decompensation event is 10 mg twice weekly. Obeticholic acid can be taken with or without food. OCA should be taken at least 4 hours before or 4 hours or more after ingesting the bile acid resin if the patient is on a bile-acid binding resin.[12]

OCA with doses varying from the FDA approved are also being evaluated. A double-blind study with patients with PBC that had an inadequate response to UDCA demonstrated that once-daily doses of OCA ranging from 10 to 50 mg for three months improved ALP levels γ-glutamyl transpeptidase and alanine aminotransferase.[13] Similarly, another study demonstrated significant improvement in the ALP levels and other biochemical markers with OCA 10 mg and 50 mg as monotherapy.[14] It should be noted that the side effect of pruritus increased dose-dependently, and the 10 mg dosage had more tolerability and fewer discontinuations.[14]

There is limited human data on the use of OCA during pregnancy, lactation, and in the pediatric population.

Adverse Effects

The most common adverse effects include pruritus, fatigue, and abdominal pain/discomfort. Other reported side effects include rash, oropharyngeal pain, dizziness, constipation, arthralgia, dyslipidemia, headache, eczema, depression, hypersensitivity reactions, and thyroid function abnormality.[1][12] The incidence of pruritus has been shown to increase dose-dependently and is higher when OCA is used as monotherapy; however, if a patient is on OCA for three months without pruritus, the side effect is unlikely to occur.[15][16][17] 

If pruritus does occur, it can be managed by adding bile acid sequestrants, antihistamines, dose reduction, or temporary dosing interruption.[15] Esophageal varices and ascites were also shown to occur as hepatic adverse events in a 3-year interim analysis of patients in the POISE trial.[18]

Obeticholic acid has also been associated with decreases in high-density lipoprotein cholesterol and triglycerides and increases in low-density lipoprotein cholesterol.[11][19][20][21] However, a double-blind, placebo-controlled study on patients with NASH showed the atorvastatin could be used along with OCA to mitigate LDL changes.[22]

In patients with decompensated cirrhosis or Child-Pugh B or C hepatic impairment, when dosed more frequently than the recommended starting dosage of 5 mg once weekly, hepatic decompensation and failure cases fatal have been reported in the postmarketing reports. In patients with PBC with decompensated cirrhosis or Child-Pugh Class B, Child-Pugh Class C, it is essential to follow dosage guidelines. 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 done on patients with PBC revealed that for the 10 mg dose, liver-related adverse effects were 5.2 per 100 patient exposure years (PEY) versus 2.4 for the placebo group. Liver-related adverse effects for the 25 mg group were 19.8 per 100 PEY and 54.5 per 100 PEY for the 50 mg group.[1] It is important to monitor the patient's liver function while on OCA and develop potential liver-related adverse reactions.

Patients that experience paradoxical worsening of liver disease, worsening enzyme elevations, or evidence of hepatic decompensation should discontinue OCA.[1] Patients with cirrhosis presenting with portal hypertension should also discontinue OCA.[23]

Contraindications

Obeticholic acid is contraindicated in patients with complete biliary obstruction.

Inhibitors of the bile salt efflux pump (BSEP) such as cyclosporine should normally be avoided when the patient takes OCA to prevent the buildup of conjugated bile salts in the liver. However, if BSEP inhibitors are necessary, transaminases and bilirubin should be monitored.

Monitoring

It is important to routinely monitor the patient's response, tolerability, and PBC disease progression. Also, continually evaluate Child-Pugh classification as dosage adjustments may be required with changes in classification. Monitoring liver function, including serum bilirubin, ALT, AST, and alkaline phosphatase, can be done 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 has been associated with reductions in high-density lipoprotein cholesterol and increases in low-density lipoprotein cholesterol. Serum lipid levels should be monitored during treatment. International Normalized Ratio (INR) should be monitored for necessary dosage adjustments as OCA is associated with decreasing INR for patients taking warfarin.[12]

Inhibitors of bile salt efflux pump (BSEP) should be avoided using OCA. However, if BSEP inhibitors are necessary, it is important to monitor serum transaminases and bilirubin. Obeticholic acid has the potential for increasing the exposure of CYP1A2 substrates. Hence the drug concentrations should be monitored in CYP1A2 substrates with narrow therapeutic indexes such as theophylline and tizanidine.[12]

Toxicity

In 2018, the FDA issued black box warnings against the use of OCA as it potentiated the deterioration of liver functions in patients with advanced liver disease and cirrhosis. Furthermore, it was found to fatally exacerbate hepatic decompensation and failure in patients presenting with PBC along with decompensated cirrhosis in whom the OCA was administered at levels higher than normal.[24]

In case of overdosage, the FDA recommends closely monitoring the patient and providing appropriate care.

Administration of OCA to patients awaiting laparoscopic cholecystectomy was found to increase gallbladder cholesterol saturation and bile acid hydrophobicity. This, along with an increase in FGF-19, may exacerbate gallstone formation risk.[25]

It is recommended that OCA be administered only in patients in whom UDCA alone is not enough or who are intolerant to UDCA.

Enhancing Healthcare Team Outcomes

OCA is a relatively new pharmacologic agent for use in populations with pathologies with few available pharmacologic treatments. It is imperative to educate clinicians, administrators, patients, and all healthcare professionals regarding its use and indications. The lack of long-term trials and data also merits continuing medical education for professionals and patients alike, as there may be new data and evidence regarding long-term treatment outcomes and adverse events. Therefore, a proper physician practice with differing dosages, patient monitoring, and treatment discontinuation is necessary. Also, it is important to monitor patient comorbidities such as concomitant renal failure, progressive liver fibrosis leading to clinical stigmata of cirrhosis, and biliary ductal obstruction.

Current FDA guidelines approve OCA for the treatment of PBC in patients who have failed treatment or are unable to tolerate UDCA. The FDA recommends routine monitoring of patients on OCA for PBC disease progression with laboratory and clinical assessments to determine whether dosage adjustment is needed. Patients with progression from Child-Pugh Class A to Class B or C will need a dose reduction. Close monitoring is also recommended for patients at increased risk of hepatic decompensation, including but not limited to those with worsening liver function tests and coagulation testing such as INR. The physicians and health care unit must use their discretion in 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.

The clinical trials on the efficacy of OCA against PBC, PSC, NAFLD, NASH, and Type-II diabetes have all shown promising results. These reports suggest that OCA, whether administered either as a monotherapy or in conjunction with conventional therapy, may effectively manage and treat these diseases. The efficacy of OCA against various other hepatic and pancreatic-related disorders warrants more studies.