Odevixibat

Indications

Odevixibat is authorized for use in managing·h progressive familial intrahepatic cholestasis (PFIC). The medication is approved by the FDA for patients aged three months and older, while Health Canada endorses its use for those aged six months and above. Additionally, odevixibat is indicated for treating·holestatic pruritus in children aged 12 months and older with Alagille Syndrome. It should be noted that individuals with PFIC type 2 who have ABCB11 variants may not experience therapeutic benefits from odevixibat, as these patients lack a functional bile salt export pump.

Pharmacodynamics

Odevixibat, also known as A4250, functions as an ileal sodium/bile acid cotransporter inhibitor. It is specifically designed to alleviate pruritus in patients with PFIC who are older than three months. The drug is administered once daily due to its moderate duration of action. Odevixibat possesses a wide therapeutic index, demonstrated by the administration of sing·hile the recommended maximum therapeutic dose is 6 mg daily. Healthcare providers should inform patients of potential side effects, including·hea, and deficiencies in fat-soluble vitamins.

Absorption

Following·he oral administration of a 7.2 mg sing·hes a maximum concentration (Cmax) of 0.47 ng·h an area under the curve (AUC0-24h) of 2.19 h*ng·hy that most adult and pediatric patients receiving·herapeutic doses typically exhibit undetectable plasma concentrations of the drug.

Metabolism

Odevixibat is primarily excreted unchang·h only a minor portion undergoing·hydroxylation in vitro. The structure of this metabolite has not been a primary focus for characterization, as clinical trials aimed to identify metabolites accounting·han 10% of the dose present in plasma, urine, or feces. To date, no metabolites have been identified at such significant concentrations.

Mechanism of Action

Odevixibat functions as a reversible inhibitor of the ileal sodium/bile acid cotransporter, a glycoprotein responsible for the reabsorption of 95% of bile acids in the distal ileum. By inhibiting this transporter, odevixibat effectively reduces bile acid reabsorption. Clinical studies have demonstrated that administering odevixibat at a dose of 3 mg once daily for one week results in a 56% reduction in bile acid area under the curve, while a 1.5 mg daily dose achieves a 43% reduction. This decreased reabsorption of bile acids subsequently leads to a decline in the stimulation of the farnesoid X receptor (FXR), thereby reducing the expression of fibroblast growth factor 19 (FGF19). As a result, the binding of FGF19 to its receptor, FGF4R, is diminished, which in turn lessens the inhibition of bile acid synthesis. This process not only aids in managing cholestasis but also contributes to lowering low-density lipoprotein levels due to the augmented synthesis of bile acids that are not reabsorbed in the intestine. It is important to note that patients with certain forms of PFIC type 2, characterized by a non-functional or absent bile salt export pump, are not expected to benefit from odevixibat treatment.