Obeticholic Acid

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

Warning

H315 (40%): Causes skin irritation [Warning Skin corrosion/irritation]

P203, P260, P261, P264, P264+P265, P271, P280, P302+P352, P304+P340, P305+P351+P338, P318, P319, P321, P332+P317, P337+P317, P362+P364, P403+P233, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 5 reports by companies from 4 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

In multiple preregistration clinical trials, obeticholic acid was found to decrease serum enzyme elevations in a high proportion of patients with different liver diseases. Instances of paradoxical worsening of liver disease or further increases in serum ALT or AST were not reported. However, the product label for obeticholic acid includes warnings that serious liver related adverse events occurred more commonly with active therapy than with placebo treatment. In a pooled analysis of 3 placebo controlled trials in patients with primary biliary cholangitis, liver related adverse events were 5.2 per 100 patient exposure years with 10 mg and 2.4 with placebo. Even higher rates occurred with higher doses of obeticholic acid: 19.8 per 100 patient years for 25 mg daily and 54.5 for 50 mg daily. The clinical features, timing of onset, pattern of enzyme elevations and course of these events were not described in detail. Within a little over a year after approval of obeticholic acid as therapy for primary biliary cholangitis, the FDA published a warning letter stating that they had received notification of 19 deaths and 11 cases of severe liver injury in patients taking obeticholic acid, most but not all of whom had preexisting cirrhosis (Case 1). More recently, severe instances of hepatic decompensation have been reported in patients with both primary biliary cholangitis as well as primary sclerosing cholangitis, two similar chronic cholestatic liver diseases.

The most common adverse effects associated with OCA 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. 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.

Drug Induced Liver Injury Rank (DILIrank 2.0)

Obeticholic acid

vMost-DILI-concern

8

Box warning

DOI:10.1016/j.drudis.2016.02.015

A05AA04

A - Alimentary tract and metabolism

QA - Alimentary tract and metabolism

The activation of the FXR by obeticholic acid acts to reduce the synthesis of bile acids, inflammation, and the resulting hepatic fibrosis. This may increase the survival of patients with PBC, but to date, an association between obeticholic acid and survival in PBC has not been established.

Primary biliary cirrhosis is an autoimmune process by which the bile ducts and liver are damaged progressively, leading to fibrosis and cirrhosis. Bile acids increase the risk of damage and fibrosis to the damaged bile ducts. Obeticholic acid is a potent agonist of the farnesoid X receptor, which serves to regulate the hepatic metabolism of bile and cholesterol. This drug acts by binding to the farnesoid X receptor (FXR), found in the nucleus of liver and intestinal cells, which in turn increases liver bile flow, suppressing its production and decreasing hepatocyte exposure to excess levels of bile with cholestasis. Cholestasis is a process that normally causes inflammation and cirrhosis of the liver.

The metabolism of obeticholic acid occurs in the liver. Obeticholic acid is conjugated with glycine or taurine, followed by secretion into bile. The conjugates are then absorbed in the small intestine and then re-enter the liver via enterohepatic circulation. The intestinal microbiota in the ileum converts conjugated obeticholic acid in a deconjugated form that may be either reabsorbed or eliminated. Glycine conjugates account for 13.8% of the metabolites and taurine conjugates account for 12.3%. Another metabolite, 3-glucuronide, may also be formed, but displays little pharmacological activity.

0462Z4S4OZ

OBETICHOLIC ACID

Established Pharmacologic Class [EPC] - Farnesoid X Receptor Agonist

Mechanisms of Action [MoA] - Farnesoid X Receptor Agonists

Obeticholic acid is a Farnesoid X Receptor Agonist. The mechanism of action of obeticholic acid is as a Farnesoid X Receptor Agonist.

Obeticholic acid is absorbed in the gastrointestinal tract. The Cmax of obeticholic acid occurs at approximately 1.5 hours after an oral dose and ranges from 28.8-53.7 ng/mL at doses of 5-10mg. The median Tmax for both the conjugates of obeticholic acid is about 10 hours. One product monograph reports a Tmax of 4.5h for both 5 and 10mg doses. The AUC ranged from 236.6-568.1 ng/h/mL with 5mg to 10 mg doses.

About 87% of an orally administered dose is accounted for in the feces. Less than 3% of the dose can be recovered in the urine.

The volume of distribution of obeticholic acid is 618 L.

Clearance information for obeticholic acid is not readily available in the literature.