curonide 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%.
Dose/Time proportionality
Following multiple-dose administration of 5, 10, and 25 mg once daily for 14 days, systemic exposures of obeticholic acid increase dose proportionally. Exposures of glyco- and tauro-obeticholic acid, and total obeticholic acid increase more than proportionally with dose.
Special populations
Elderly
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.
Paediatric population
No pharmacokinetic studies were performed with obeticholic acid in patients less than 18 years of age.
Gender
Population pharmacokinetic analysis indicated that gender does not influence obeticholic acid pharmacokinetics.
Race
Population pharmacokinetic analysis indicated that race is not expected to influence obeticholic acid pharmacokinetics.
Renal impairment
Obeticholic acid has minimal renal elimination with less than 3% of the dose recovered in urine. Based on population pharmacokinetic analysis, renal function did not have a meaningful effect on the pharmacokinetics of obeticholic acid.
Hepatic impairment
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. Therefore, a modified dose regimen for patients with moderate or severe hepatic impairment is required to achieve plasma exposure levels similar to patients with no hepatic impairment (see section 4.2).
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.
5.3 Preclinical safety data
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- |
