OBETOLIC 5

Description

PHARMACOLOGICAL PROPERTIES:

Pharmacodynamic properties:

Mechanism of action

Obeticholic acid is a selective and potent agonist for the farnesoid X receptor (FXR), a nuclear receptor expressed at high levels in the liver and intestine. FXR is thought to be a key regulator of bile acid, inflammatory, fibrotic, and metabolic pathways. FXR activation decreases the intracellular hepatocyte concentrations of bile acids by suppressing de novo synthesis from cholesterol, as well as, by increasing transport of bile acids out of the hepatocytes. These mechanisms limit the overall size of the circulating bile acid pool while promoting choleresis, thus reducing hepatic exposure to bile acids.

Pharmacodynamic effects

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.

Pharmacokinetic properties:

Absorption

Obeticholic acid is absorbed with peak plasma concentrations (Cmax) occurring at a median time (tmax) of approximately 2 hours. Co-administration with food does not alter the extent of absorption of obeticholic acid.

Distribution

Human plasma protein binding of obeticholic acid and its conjugates is greater than 99%. The volume of distribution of obeticholic acid is 618 L. The volume of distributions of glyco- and tauro-obeticholic acid has not been determined.

Biotransformation

Obeticholic acid is conjugated with glycine or taurine in the liver and secreted into bile. These glycine and taurine conjugates of obeticholic acid are absorbed in the small intestine leading to enterohepatic recirculation. The conjugates can be deconjugated in the ileum and colon by intestinal microbiota, leading to the conversion to obeticholic acid that can be reabsorbed or excreted in faeces, the principal route of elimination.

After daily administration of obeticholic acid, there was accumulation of the glycine and taurine conjugates of obeticholic acid which have in vitro pharmacological activities similar to the parent drug. The metabolite-to -parent ratios of the glycine and taurine conjugates of obeticholic acid were 13.8 and 12.3, respectively, after daily administration. An additional third obeticholic acid metabolite, 3-glucuronide is formed but is considered to have minimal pharmacologic activity.

Elimination

After administration of radiolabeled obeticholic acid, greater than 87% is excreted in faeces. Urinary excretion is less than 3%.

 

THERAPEUTIC CLASS: Obeticholic acid (OCA) is a first-in-class farnesoid X receptor agonist and ant fibrotic agent.

 

CLINICAL PARTICULARS:

Therapeutic Indication:

Obeticholic acid is a bile acid analog and farnesoid X receptor agonist used to treat primary biliary cholangitis in adult patients with inadequate clinical response or intolerance to UDCA.

Posology and method of Administration:

Posology:

Non-Cirrhotic or Child-Pugh Class A

Starting Dose: 5 mg once daily

Maximum Dose: 10 mg once daily

Child-Pugh Class B or C or Decompensated Cirrhotic

Starting Dose: 5 mg once Weekly

Maximum Dose: 10 mg twice weekly (at least 3 days apart)

Method of administration

For oral administration:

Tablets should be swallowed intact and should not be crushed, chewed or broken into pieces prior to administration with or without food.

Missed Dose

If one dose is missed, this dose should be omitted and the next dose should be taken at the usual time with a meal. Do not take a double dose to make up for a forgotten dose.

 

CONTRAINDICATIONS:

Obeticholic acid is contraindicated in patients with:

• Decompensated cirrhosis (e.g., Child-Pugh Class B or C) or a prior decompensation event
• Compensated cirrhosis who have evidence of portal hypertension (e.g., ascites, gastro esophageal varices, persistent thrombocytopenia)
• Complete biliary obstruction

 

SIDE EFFECTS:

Dizziness, Palpitations, Oropharyngeal pain, Constipation, Eczema, Rash, Arthralgia, Oedema peripheral, Pyrexia, Fatigue, Pruritus, Abdominal pain and discomfort.

 

SPECIAL WARNINGS AND PRECAUTIONS FOR USE:

• Hepatic decompensation and failure, sometimes fatal or resulting in liver transplant have been reported with Obetic treatment in PBC patients with cirrhosis either compensated or decompensated.

 

OTHER MEDICINES AND OBETICHOLIC ACID TABLETS:

The effect of the following drugs can be influenced (interactions):

• Hepatotoxicity was observed in the Obetic clinical trials.

 

PREGNANCY AND BREAST-FEEDING

Pregnancy: As a precautionary measure, it is preferable to avoid the use of obeticholic acid during pregnancy.

Breast-feeding: There is no information on the presence of obeticholic acid in human milk, so it can be used during breast feeding.

 

DRIVING AND USING MACHINES

Obeticholic acid has no or negligible influence on the ability to drive and use machines.