Chemical formula: C₂₆H₄₄O₄ Molecular mass: 420.625 g/mol PubChem compound: 447715
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.
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.
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 volumes of distribution of glyco- and tauro-obeticholic acid have not been determined.
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.
After administration of radiolabeled obeticholic acid, greater than 87% is excreted in faeces. Urinary excretion is less than 3%.
Following multiple-dose administration of 5, 10, and 25 mg once daily for 14 days, systemic exposures of obeticholic acid increased dose proportionally. Exposures of glyco- and tauro-obeticholic acid, and total obeticholic acid increase more than proportionally with dose.
There are limited pharmacokinetic data in elderly patients (≥65 years). Population pharmacokinetic analysis, developed using data from patients up to 65 years old, indicated that age is not expected to significantly influence obeticholic acid clearance from the circulation.
No pharmacokinetic studies were performed with obeticholic acid in patients less than 18 years of age.
Population pharmacokinetic analysis indicated that gender does not influence obeticholic acid pharmacokinetics.
Population pharmacokinetic analysis indicated that race is not expected to influence obeticholic acid pharmacokinetics.
In a dedicated single-dose pharmacokinetic study using 25 mg of obeticholic acid, plasma exposures to obeticholic acid and its conjugates were increased by approximately 1.4- to 1.6-fold in subjects with mild (modification of diet in renal disease [MDRD] eGFR ≥60 and <90 mL/min/1.73 m²), moderate (MDRD eGFR ≥30 and <60 mL/min/1.73 m²) and severe (MDRD eGFR ≥15 and <30 mL/min/1.73 m²) renal impairment compared to subjects with normal renal function. This modest increase is not considered to be clinically meaningful.
Obeticholic acid is metabolised in the liver and intestines. The systemic exposure of obeticholic acid, its active conjugates, and endogenous bile acids is increased in patients with moderate and severe hepatic impairment (Child-Pugh Class B and C, respectively) when compared to healthy controls.
The impact of mild hepatic impairment (Child-Pugh Class A) on the pharmacokinetics of obeticholic acid was negligible, therefore, no dose adjustment is necessary for patients with mild hepatic impairment.
In subjects with mild, moderate and severe hepatic impairment (Child-Pugh Class A, B, and C, respectively), mean AUC of total obeticholic acid, the sum of obeticholic acid and its two active conjugates, increased by 1.13-, 4- and 17-fold, respectively, compared to subjects with normal hepatic function following single-dose administration of 10 mg obeticholic acid.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, and toxicity to fertility, reproduction and development.
Oral administration of obeticholic acid above the NOAEL to mice, rats, and dogs in pivotal, repeat dose toxicity studies resulted primarily in effects on the hepatobiliary system. These included increased liver weights, alterations in serum chemistry parameters (ALT, AST, LDH, ALP, GGT, and/or bilirubin), and macroscopic/microscopic alterations. All changes were reversible with discontinued dosing, and are consistent with and predict the dose-limiting toxicity in humans (systemic exposure at NOAEL was up to 24-fold higher than that seen at the maximum recommended human dose). In a pre- and post-natal toxicity study in rats, the tauro-conjugate of obeticholic acid was found in pups nursing from dams dosed with obeticholic acid.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
