Introduction

Odevixibat is an orally available inhibitor of the ilieal bile salt transporter which is used to treat severe pruritus in patients with cholestatic liver disease such as progressive familial intrahepatic cholestasis. Odevixibat is associated with transient serum enzyme elevations 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

Odevixibat (oh” de vix' i bat) is a small molecule inhibitor of the ileal bile acid transporter and is used to treat the pruritus of severe cholestatic liver diseases such as progressive familial intrahepatic cholestasis (PFIC). Inhibition of the bile acid transporter blocks the reabsorption of bile salts in the terminal ileum and thereby lowers levels of serum bile acids that are raised in patients with PFIC. Three major forms of PFIC are known, due to genetic abnormalities in various hepatic biliary transporters: PFIC-1 due to the ATP8B1 protein (gene name FIC1), PFIC-2 to the bile acid exporter protein (BSEP: gene name ABCB11), and PFIC-3 to multi-drug resistant-3 protein (MDR3: gene name ABCB4). Children with PFIC develop progressive cholestatic liver injury with marked increases in serum total bile acids, variable degrees of symptoms of pruritus (itching) and fatigue which can be disabling. Most children have progressive cholestatic liver injury and eventually require liver transplantation. Odevixibat was approved for use in the United States in 2021 as therapy of severe pruritus in children with PFIC. It is under evaluation as therapy for other severe forms of cholestatic liver injury such as Alagille syndrome and biliary atresia, but initially was not formally approved for those uses. Odevixibat is available under the brand name Bylvay in capsules of 400 µg and 1200 µg to be swallowed as well as in 200 µg and 600 µg capsules to be opened and sprinkled on soft food as oral pellets. The recommended initial dose is 40 µg/kg once daily which can be increased to 100 µg/kg daily based upon tolerance and effect. Odevixibat therapy can be associated with symptoms of diarrhea, abdominal pain, nausea and vomiting, and serum aminotransferase elevations, but these adverse events are also common in untreated children with PFIC. Odevixibat acts locally on the bile acid transporter in the distal ileum and has little systemic absorption. Severe adverse events are rare, but long term therapy can be associated with fat-soluble vitamin deficiencies for which reason prospective monitoring of serum levels of these vitamins is recommended.

Hepatotoxicity

In trials of odevixibat in children with cholestatic liver diseases, serum ALT elevations of greater than 3 times ULN arose in 8% to 11% of treated participants and were particularly common with long term therapy. However, children with PFIC typically have serum ALT and AST elevations, and it was difficult to establish whether mild-to-moderate serum enzyme elevations were due to odevixibat therapy or to the spontaneous fluctuations that occur with the underlying disease. Clinically apparent liver injury with jaundice or hepatic decompensation has not been reported in children treated with odevixibat, although the total clinical experience with its use is limited.

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

Mechanism of Injury

The mechanism by which odevixibat might cause liver injury is not known. It has little oral absorption and systemic levels are minimal. The serum aminotransferase elevations that occur with therapy may be due to its effects on absorption of fat soluble vitamins or medications, or to fluxes in the bile acid pool, or to changes in the intestinal microbiome.

Outcome and Management

While chronic therapy with odevixibat can be associated with mild-to-moderate serum aminotransferase elevations, it has not been linked to cases of clinically apparent liver injury. Because of the frequency of enzyme elevations detected during therapy, the product label for odevixibat recommends obtaining baseline liver tests before initiation of treatment and monitoring levels during therapy. Any ALT or AST elevation associated with symptoms or jaundice should lead to discontinuation. Moderate elevations above baseline without symptoms, however, can be managed with dose modification or interruption. There is no known cross sensitivity of the hepatic injury from odevixibat 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 maralixibat, another FDA approved ileal bile acid transporter inhibitor.

Drug Class: Ileal Bile Acid Transporter (IBAT) Inhibitors

Other Drugs in the Subclass, Pruritus Agents: Maralixibat