Introduction

Maralixibat is an orally available inhibitor of the ileal bile salt transporter which is used to treat severe pruritus in patients with cholestatic liver disease including Alagille syndrome without cirrhosis. Maralixibat is associated with transient serum enzyme fluctuations particularly with long term therapy but has not been linked to instances of clinically apparent liver injury with jaundice, although experience with its use has been limited.

Background

Maralixibat (mar" a lix' i bat) is an small molecule inhibitor of the ileal bile acid transporter that is used to treat pruritus in patients with cholestatic liver disease such as Alagille syndrome, a severe inherited disease marked by cholestatic liver injury and severe itching. The ileal bile acid transporter is responsible for the uptake of bile salts from the terminal ileum, an essential step in the entero-hepatic circulation of bile acids. Interruption of this enterohepatic circulation results in a decrease in serum bile acid levels and decline in the whole body bile acid pool, both of which are increased in patients with cholestatic liver disease and are associated with the symptom of pruritus. In animal models of cholestatic liver disease, administration of maralixibat resulted in marked decreases in serum bile acid levels, improvements in liver histology, and decrease in resultant hepatic fibrosis. In small open-label clinical trials in children with Alagille syndrome without cirrhosis, maralixibat resulted in improvements in bile acid levels, symptoms of pruritus, sleep disturbance and general well being. These improvements were maintained with long term treatment. Maralixibat was approved for use in patients with Alagille syndrome and severe pruritus in 2021. It continues to be evaluated for efficacy and safety in other cholestatic liver diseases. Maralixibat is administered orally, acts locally on the ileal bile acid transporter, and has little systemic absorption. Maralixibat is available as a solution of 9.5 µg/mL under the brand name Livmarli. The recommended starting dose is 190 µg/kg once daily, which can be increased to 380 µg/kg daily after a week, based upon tolerance. Adverse events may include diarrhea, nausea and bloating, and elevations in serum aminotransferase levels, particularly with prolonged therapy and with higher doses. Prolonged therapy can result in deficiencies in fat soluble vitamins, levels of which should be monitored during therapy. Severe adverse events are uncommon but can include gastrointestinal bleeding and bone fractures. Most of these side effects also occur in patients with Alagille syndrome who are not treated with ileal bile salt transporter inhibitors and the role of maralixibat in causing these symptoms is not always clear.

Hepatotoxicity

In trials of maralixibat in children with Alagille syndrome, serum ALT levels rose to greater than 3 times ULN in 24% of patients and above 5 times ULN in 2%. The ALT elevations led to dose modification, interruption or therapy or early discontinuation in up to 10% of patients. Children with Alagille syndrome and other pediatric cholestatic liver diseases typically have serum aminotransferase elevations in the range of 2 to 5 times ULN, and it is can be difficult to distinguish between spontaneous fluctuations in enzyme levels due to the underlying disease vs effects of maralixibat therapy. In most instances, therapy can be continued despite the serum enzyme elevations, at least at a reduced dosage. There have been no reports of clinically apparent liver injury with jaundice attributed to maralixibat therapy, but it has had limited general clinical use.

Likelihood score: E* (suspected but unproven cause of clinically apparent liver injury).

Mechanism of Injury

The mechanism by which maralixibat might cause liver injury is not known. It has minimal intestinal absorption and is unlikely to have a direct toxic effect on the liver. The serum aminotransferase elevations that occur with therapy may be due to its effects on absorption of fat soluble vitamins, nutrients or medications, or to fluxes in the bile acid pool, or to changes in the intestinal microbiome.

Outcome and Management

While chronic therapy with maralixibat can be associated with mild-to-moderate serum aminotransferase elevations, it has not been linked to any cases of clinically apparent liver injury. Because of the frequency of enzyme elevations detected during therapy, the product label for maralixibat recommends obtaining baseline liver tests before initiation of treatment. Any subsequent rise in ALT or AST values associated with symptoms or jaundice should lead to prompt discontinuation of maralixibat. Patients with persistent elevations above 3 times ULN without symptoms or jaundice should be assessed for other causes of liver injury. If no other cause of the elevations is found, the dose of maralixibat should be reduced or therapy interrupted. There is no known cross sensitivity of the hepatic injury from maralixibat with other agents used to treat pruritus. Because of the similarity in chemical structure and mechanism of action, there may be cross sensitivity to side effects with odevixibat, another FDA approved ileal bile acid transporter inhibitor.

Drug Class: Ileal Bile Acid Transporter (IBAT) Inhibitors

Other Drugs in the Subclass, Pruritus Agents: Odevixibat