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General Description:

Odevixibat, identified by CAS number 501692-44-0, is a notable compound with significant therapeutic applications. Odevixibat, or A4250, is an ileal sodium/bile acid cotransporter inhibitor indicated for the treatment of pruritus in patients older than 3 months, with progressive familiar intrahepatic cholestasis (PFIC). Odevixibat is the first approved non-surgical treatment option for PFIC. Previous therapies for PFIC included a bile acid sequestrant such as . Odevixibat was granted FDA approval on 20 July 2021.

Indications:

This drug is primarily indicated for: Odevixibat is indicated for the treatment of pruritus in patients older than 3 months, with progressive familiar intrahepatic cholestasis (PFIC). It may not be effective in PFIC type 2 with ABCB11 variants. These patients lack a functional bile salt export pump. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Odevixibat undergoes metabolic processing primarily in: Odevixibat is largely unmetabolized, however a small amount is metabolized _in vitro_ by mono-hydroxylation. The exact structure of the metabolite has not been characterized as a primary endpoint of the clinical trial was to characterize the structure of metabolites accounting for >10% of the dose in plasma, urine, or feces. No metabolites have been identified at such a high concentration. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Odevixibat are crucial for its therapeutic efficacy: A 7.2 mg single oral dose of odevixibat in adults reaches a C_max of 0.47 ng/mL, with an AUC_0-24h of 2.19 h\*ng/mL. The majority of adult and pediatric patients, given a therapeutic dose, do not have detectable plasma concentrations of odevixibat. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Odevixibat is an important consideration for its dosing schedule: A 7.2 mg oral dose of odevixibat has a mean half life of 2.36 hours in adults. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Odevixibat exhibits a strong affinity for binding with plasma proteins: Due to the low systemic abosrption of odevixibat, plasma protein binding studies could not be performed _in vivo_. Odevixibat is >99% protein bound _in vitro_. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Odevixibat from the body primarily occurs through: Odevixibat is 82.9% recovered in the feces and <0.002% recovered in the urine. The dose recovered in the feces is 97% unchanged parent compound. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Odevixibat is distributed throughout the body with a volume of distribution of: The majority of adult and pediatric patients, given a therapeutic dose, do not have detectable plasma concentrations of odevixibat. Therefore, a volume of distribution has not been calculated. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Odevixibat is a critical factor in determining its safe and effective dosage: The majority of adult and pediatric patients, given a therapeutic dose, do not have detectable plasma concentrations of odevixibat. Therefore, the clearance has not been calculated. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Odevixibat exerts its therapeutic effects through: Odevixibat, or A4250, is an ileal sodium/bile acid cotransporter inhibitor indicated for the treatment of pruritus in patients older than 3 months, with progressive familiar intrahepatic cholestasis (PFIC). It has a moderate duration of action as it is given once daily. Odevixibat has a wide therapeutic index as patients were given single doses up to 10 mg while the maximum therapeutic dose is 6 mg daily. Patients should be counselled regarding the risks of elevated liver function tests, diarrhea, and fat soluble vitamin defiencies. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Odevixibat functions by: Progressive familiar intrahepatic cholestasis (PFIC) is a group of autosomal recessive disorders leading to cholestasis, fibrosis, and eventually a need for liver transplantation. Patients with PFIC require liver transplants or develop hepatocellular carcinomas in their first few years of life. Many of these patients experience severe pruritus. The exact mechanism of pruritus is PFIC is not known, but lower concentrations of bile acids have been shown to reduce pruritus. Patients with certain forms of PFIC type 2, associated with a non-functional or absent bile salt export pump, are not expected to benefit from odevixibat treatment. The ileal sodium/bile acid cotransporter is a transport glycoprotein responsible for reabsorption of 95% of bile acids in the distal ileum. Odevixibat is a reversible inhibitor of the ileal sodium/bile acid contransporter. Patients taking odevixibat for a week experienced a 56% reduction in bile acid area under the curve with a 3 mg once daily dose. A 1.5 mg daily dose lead to a 43% reduction in bile acid area under the curve. The decreased reabsorption of bile acids, leads to reduced stimulation of FXR, which reduces expression of FGF19, reducing binding of FGF19 to FGF4R, decreasing inhibition of bile acid synthesis. Further synthesis of bile acids that will not be reabsorbed in the intestine contributes to lowering low density lipoprotein levels. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Categories:

Odevixibat is categorized under the following therapeutic classes: Acids, Acyclic, Alimentary Tract and Metabolism, Benzazepines, Bile and Liver Therapy, Bile Therapy, Fatty Acids, Fatty Acids, Volatile, Heterocyclic Compounds, Fused-Ring, Ileal bile acid transport inhibitor, Ileal Bile Acid Transporter Inhibitor, Lipids, P-glycoprotein substrates. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.