Ocaliva (Page 4 of 7)

11 DESCRIPTION

OCALIVA is a farnesoid X receptor (FXR) agonist. Chemically, obeticholic acid is 3α,7α-dihydroxy-6α-ethyl-5β-cholan-24-oic acid. It is a white to off-white powder. It is soluble in methanol, acetone and ethyl acetate. Its solubility in water is pH dependent. It is slightly soluble at low pH and very soluble at high pH. Its chemical formula is C26 H44 O4 , the molecular weight is 420.63 g/mol, and the chemical structure is:

Chemical Structure

OCALIVA tablets are supplied in 5 mg and 10 mg strengths for oral administration. Each tablet contains obeticholic acid as the active ingredient and the following inactive ingredients: microcrystalline cellulose, sodium starch glycolate, and magnesium stearate. The film coating is Opadry II (Yellow) containing polyvinyl alcohol-part hydrolyzed, titanium dioxide, macrogol (polyethylene glycol 3350), talc, and iron oxide yellow.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Obeticholic acid is an agonist for FXR, a nuclear receptor expressed in the liver and intestine. FXR is 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 increased 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.

12.2 Pharmacodynamics

Dose Titration

In Trial 1, ALP reduction was observed to plateau at approximately 3 months in most patients treated with OCALIVA 5 mg once daily. Increasing the dosage of OCALIVA to 10 mg once daily based on tolerability and response provided additional reduction in ALP in the majority of patients [see Dosage and Administration (2.2), Clinical Studies (14)].

Pharmacodynamic Markers

In Trial 1, administration of OCALIVA 10 mg once daily was associated with a 173% increase in concentrations of FGF-19, an FXR-inducible enterokine involved in bile acid homeostasis, from baseline to Month 12. Concentrations of cholic acid and chenodeoxycholic acid were reduced 2.7 micromolar and 1.4 micromolar, respectively, from baseline to Month 12. The clinical relevance of these findings is unknown.

Cardiac Electrophysiology

At a dose of 10-times the maximum recommended dose, OCALIVA does not prolong the QT interval to any clinically relevant extent.

12.3 Pharmacokinetics

Absorption

Following multiple oral doses of OCALIVA 10 mg once daily, peak plasma concentrations (Cmax ) of obeticholic acid occurred at a median time (Tmax ) of approximately 1.5 hours. The median Tmax for both the glyco- and tauro-conjugates of obeticholic acid was 10 hours. Coadministration with food did not alter the extent of absorption of obeticholic acid [see Dosage and Administration (2.5)].

Following multiple-dose administration of OCALIVA 5, 10, and 25 mg once daily (2.5-times the highest recommend dosage) for 14 days, systemic exposures of obeticholic acid increased dose proportionally. Exposures to glyco-obeticholic acid and tauro-obeticholic acid, and total obeticholic acid (the sum of obeticholic acid and its two active conjugates) increased more than proportionally with dose. The steady-state systemic exposure (AUC0-24h ) achieved on Day 14 of total obeticholic acid was 4.2-, 6.6-, and 7.8- fold the systemic exposure (AUC0-24h ) achieved on Day 1 after 5, 10, and 25 mg once daily dosing, respectively.

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 volumes of distribution of glyco- and tauro-obeticholic acid have not been determined.

Elimination

Metabolism

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 feces, 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, obeticholic acid. 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, was formed but was considered to have minimal pharmacologic activity.

Excretion

After administration of radiolabeled obeticholic acid, about 87% of the dose was excreted in feces through biliary secretion. Less than 3% of the dose was excreted in the urine with no detection of obeticholic acid.

Specific Populations

Body weight, Age, Sex Race/Ethnicity: Based on population pharmacokinetic analysis, body weight was a significant predictor of obeticholic acid pharmacokinetics with lower obeticholic acid exposure expected with higher body weight. The body weight effect is not expected to cause a meaningful impact on efficacy. The pharmacokinetics of obeticholic acid would not be expected to be altered based on age, sex, or race/ethnicity.

Renal Impairment: In a single-dose pharmacokinetic study using 25 mg of obeticholic acid (2.5-times the highest recommended dosage), mean AUC of total obeticholic acid was increased by approximately 1.4- to 1.6-fold in subjects with mild (eGFR 60 to 89 mL/min/1.73 m2 using the modification of diet in renal disease [MDRD] equation), moderate (eGFR 30 to 59 mL/min/1.73 m2 by MDRD), and severe (eGFR 15 to 29 mL/min/1.73 m2 by MDRD) renal impairment compared to subjects with normal renal function. This increase is not considered to be clinically meaningful.

Hepatic Impairment: Obeticholic acid is metabolized in the liver. In subjects with mild, moderate, and severe hepatic impairment (Child-Pugh Class A, B, and C, respectively), the mean AUC of total obeticholic acid increased 1.1-, 4- and 17-fold, respectively, compared to subjects with normal hepatic function following single-dose administration of 10 mg OCALIVA [see Contraindications (4), Warnings and Precautions (5.1), Use in Specific Populations (8.6)].

Drug Interaction Studies

Effect of Obeticholic Acid on Other Drugs

Based on in vitro studies, obeticholic acid can inhibit CYP3A4. However, an in vivo study indicated no inhibition of CYP3A4 by obeticholic acid at the recommended dose of OCALIVA. Obeticholic acid is not expected to inhibit CYPs 2B6, 2C8, 2C9, 2C19, and 2D6, or induce CYPs 1A2, 2B6, 2C8, 2C9, 2C19, and 3A4 at the recommended dose of OCALIVA. Down-regulation of mRNA was observed in a concentration-dependent fashion for CYP1A2 and CYP3A4 by obeticholic acid and its glycine and taurine conjugates.

In vitro studies suggest that there is potential for obeticholic acid and its glycine and taurine conjugates to inhibit OATP1B1 and OATP1B3 (the clinical significance of which is unknown), but not P-gp, BCRP, OAT1, OAT3, OCT2, and MATE transporters, at the recommended dose of OCALIVA.

In vitro studies showed that obeticholic acid and its glycine and taurine conjugates inhibit BSEP in a dose dependent manner. However, an in vivo drug interaction due to inhibition of BSEP in patients using the recommended dosage regimen appears unlikely.

Induction of BSEP can occur by FXR activation by obeticholic acid and its conjugates, which are FXR agonists.

Warfarin: Concomitant administration of 25 mg warfarin as a single dose with OCALIVA 10 mg once daily resulted in 13% increase in systemic exposure to S-warfarin and 11% decrease in maximum INR [see Drug Interactions (7.2)].

Caffeine (CYP1A2 substrate): Concomitant administration of 200 mg caffeine as a single dose with OCALIVA 10 mg once daily resulted in a 42% increase in plasma AUC and 6% increase in Cmax of caffeine [see Drug Interactions (7.3)].

Omeprazole (CYP2C19 substrate): Concomitant administration of 20 mg omeprazole as a single dose with OCALIVA 10 mg once daily resulted in a 32% increase in AUC and a 33% increase in Cmax of omeprazole. The clinical significance is unknown.

No clinically relevant interactions were seen when the following drugs were administered as single doses concomitantly with OCALIVA 10 mg once daily:

Midazolam 2 mg (CYP3A4 substrate): 2% increase in AUC and Cmax of midazolam.

Dextromethorphan 30 mg (CYP2D6 substrate): 11% decrease in AUC and 12% decrease in Cmax of dextromethorphan.

Digoxin 0.25 mg (P-gp substrate): 1% increase in AUC and 3% decrease in Cmax of digoxin.

Rosuvastatin 20 mg (BCRP, OATP1B1, OATP1B3 substrate): 22% increase in AUC and a 27% increase in Cmax of rosuvastatin.

Effect of Other Drugs on Obeticholic Acid

In vitro data suggest that obeticholic acid is not metabolized to any significant extent by CYP450 enzymes.

Proton Pump Inhibitors (omeprazole): Concomitant administration of 20 mg omeprazole once daily with OCALIVA 10 mg once daily resulted in a less than 1.2-fold increase in obeticholic acid plasma exposure. This increase is not expected to be clinically meaningful. Concomitant administration of 40 mg omeprazole once daily with OCALIVA 10 mg once daily was not studied.

BSEP inhibitors: In vitro data indicate that tauro-obeticholic acid is a substrate of BSEP [see Drug Interactions (7.4)].

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