Linerixibat

Linerixibat is a reversible inhibitor of the ileal bile acid transporter (IBAT). It decreases the reabsorption of bile acids in the terminal ileum leading to their increased fecal elimination.

Cholestatic pruritus is a common symptom in patients with PBC, and the pathophysiology of pruritus in patients with PBC is not completely understood. Although the complete mechanism by which linerixibat improves pruritus in PBC patients is unknown, it may involve inhibition of the IBAT as observed by a decrease in mediators of pruritus including serum bile acids.

Linerixibat reduces total serum bile acids in healthy volunteers and PBC patients with cholestatic pruritus. In healthy volunteers, serum bile acids were reduced within 1 day of linerixibat treatment compared to placebo treatment. In Study 1, total serum bile acids were reduced from baseline over the 24-week treatment period in the linerixibat group when compared to the placebo group.

Due to the low systemic absorption of linerixibat, pharmacokinetic parameters cannot be reliably calculated at the recommended doses. Following a single dose administration of 40 mg of linerixibat, concentrations of linerixibat in healthy volunteers were below the limit of quantification (10 pg/mL) in the majority of plasma samples. Following multiple doses of linerixibat ranging from 3 mg (0.08 times the approved recommended dose) twice daily to 90 mg (2.25 times the approved recommended dose) twice daily in healthy volunteers, the majority of plasma samples were below the limit of quantification (1,000 pg/mL).

Absorption

Linerixibat is minimally absorbed following oral administration and the absolute oral bioavailability of linerixibat is 0.05%. Following a single oral administration of linerixibat 40 mg in healthy adults under fasted conditions, median T_max was 4.5 hours and mean linerixibat (%CV) C_max and AUC_0-t were 31.1 pg/mL (173) and 105 h·pg/mL (419), respectively. Following multiple doses of linerixibat 40 mg twice daily in PBC patients with cholestatic pruritus, the mean linerixibat C_max (95% CI) was 922 pg/mL (347, 1,500).

Effect of Food

Concomitant administration of a high-fat meal with a single dose of linerixibat 40 mg oral tablets delayed median T_max from 4.5 hours to 8.0 hours and resulted in decreases of 21.9% and 33.7% in AUC_0-t and C_max, respectively, compared to administration under fasted conditions in healthy adults. Pharmacokinetic parameters in the food effect study were highly variable. The effect of food on the changes of systemic exposures to linerixibat is not clinically significant. Despite the lack of clinically important pharmacokinetic effects with food, linerixibat should be administered at least 30 minutes prior to food or beverage (other than water) to allow linerixibat to enter the gastrointestinal lumen prior to release of bile acids upon eating.

Distribution

The in vitro plasma protein binding range of linerixibat was 71.0-76.4%.

Elimination

Following a single oral dose of linerixibat 90 mg (2.25 times the approved recommended dose) in healthy adults, the mean half-life (t_1/2) was 6.76 hours.

Metabolism

Following administration of oral radiolabeled linerixibat, no linerixibat metabolites were detected in plasma. Three minor oxidative metabolites were detected in feces, and each accounted for negligible radioactivity (<1%), demonstrating that linerixibat is minimally metabolized in humans.

Excretion

Following administration of oral radiolabeled linerixibat, approximately 97% of the dose was excreted in feces; approximately 0.04% of the dose was excreted in urine. More than 99% of fecal radioactivity was determined to be unchanged and unabsorbed linerixibat. Following intravenous administration of radiolabeled linerixibat, systemic linerixibat elimination was approximately 20% renal and 80% fecal.

Specific Populations

No clinically significant differences in changes of total serum bile acid concentrations were observed with linerixibat based on body weight, age, sex, or race (White, Black, or Asian).

Patients with Hepatic Impairment

Of 238 patients enrolled in Study 1, 25 (11%) patients were diagnosed with cirrhosis (F4, Child-Pugh A), out of which 13 (5%) patients received linerixibat treatment. A general trend of higher exposure of linerixibat was observed in patients with cirrhosis compared to patients without cirrhosis, although the number of patients was very small. In a pharmacokinetic study in patients with moderate hepatic impairment (Child-Pugh B), the mean AUC_(0-∞) and C_max values were approximately 13-fold and 9.4-fold higher than matched healthy patients. The clinical significance of this increase is unknown. Pharmacokinetics of linerixibat have not been evaluated in patients with severe hepatic impairment (Child-Pugh C).

Drug Interaction Studies

Effect of Bile Acid Binding Resins on Linerixibat: Approximately 78% to 95% of linerixibat was bound to cholestyramine and colesevelam in in vitro studies. Cholestyramine and colesevelam can potentially inhibit the effects of linerixibat on IBAT.

Effect of Linerixibat on Ursodeoxycholic Acid (UDCA): In a dose-ranging study, adult PBC patients received placebo or linerixibat dosages ranging from 20 mg once a day (0.25 times the recommended dosage) to 90 mg twice a day (2.25 times the recommended dosage) for 12 weeks. In this clinical trial, concomitant administration of UDCA and linerixibat had no effect on UDCA plasma concentrations but reduced concentrations of UDCA conjugates, glyco-UDCA and tauro-UDCA, at 12 weeks of therapy. The concentrations of UDCA conjugates, glyco-UDCA and tauro-UDCA, were reduced by 69% and 90%, respectively, in patients receiving concomitant administration of UDCA with linerixibat versus with placebo. However, concomitant administration of UDCA with linerixibat resulted in no clinically significant increases in ALP over 12 weeks of treatment.

In in vitro studies, linerixibat did not inhibit cytochrome P450 (CYP)s 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, and 2E1, but was an inhibitor of CYP3A4. Due to the low fraction absorbed, an interaction is not likely. Linerixibat did not induce CYPs 1A2, 2B6, and 3A4.

In in vitro studies, linerixibat did not inhibit the transporters, P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporters (OAT) 1 and 3, organic cation transporter (OCT) 2, and multidrug and toxin extrusion protein (MATE) 1 and 2K. In vitro studies suggest that there is a potential for linerixibat to inhibit organic anion transporter polypeptide 1B1 and 1B3 (OATP1B1 and OATP1B3). However, due to the low fraction absorbed, an interaction is not likely.