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General Description:

Maralixibat, identified by CAS number 716313-53-0, is a notable compound with significant therapeutic applications. Maralixibat (also known as SHP625, LUM001, and lopixibat) is an ileal bile acid transporter inhibitor, like . Maralixibat is indicated for the treatment of cholestatic pruritus in patients with Alagille syndrome, who are at least 1 year old. Previously, patients with cholestatic pruritus associated with Alagille syndrome were treated with antihistamines, , , , , and alone or in combination. No clinical trials have been performed to assess the efficacy of these treatments for cholestatic pruritus and treatments were given based on a prescriber's clinical experience. Surgical interventions such as partial external bile diversion and ileal exclusion have also been used as treatments. Maralixibat represents the first FDA-approved treatment for cholestatic pruritus in patients with Alagille syndrome. It was granted FDA approval on 29 September 2021. In October 2022, the EMA's Committee for Medicinal Products for Human Use (CHMP) recommended maralixibat be granted marketing authorization for the treatment of cholestatic pruritus in patients with Alagille syndrome: maralixibat was granted marketing authorization in Europe on 13 December 2022.

Indications:

This drug is primarily indicated for: Maralixibat is indicated in the treatment of cholestatic pruritus in patients with Alagille syndrome. It is approved for use in patients who are at least one year old in the US and two months of age and older in Europe. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Maralixibat undergoes metabolic processing primarily in: Maralixibat metabolites have not been identified in plasma, however 3 minor metabolites have been recovered in the feces. The structure of these metabolites have not been defined in the literature. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Maralixibat are crucial for its therapeutic efficacy: Maralixibat is not extensively absorbed. A single 30 mg dose of maralixibat given under fasted conditions reached a median T_max of 0.75 hours, with a mean C_max of 1.65 ± 1.10 ng/mL, and a mean AUC_last of 3.43 ± 2.13 h\*ng/mL. In pediatric patients given a dose of 380 µg/kg, the highest serum concentration was 5.93 ng/mL, but was <0.25 ng/mL in the majority of patients. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Maralixibat is an important consideration for its dosing schedule: The mean half life of maralixibat is 1.6 hours. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Maralixibat exhibits a strong affinity for binding with plasma proteins: Maralixibat is 91% bound to plasma proteins _in vitro_. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Maralixibat from the body primarily occurs through: A 5 mg radiolabelled dose of maralixibat is 73% eliminated in feces and 0.066% eliminated in urine. 94% of the dose recovered in the feces was as the unmetabolized parent compound. <3% of the total dose is metabolized. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Pharmacodynamics:

Maralixibat exerts its therapeutic effects through: Maralixibat is indicated in the treatment of cholestatic pruritus in patients with Alagille syndrome who are at least 1 year old. It has a moderate duration of action as it is given once daily, and a wide therapeutic index as patients have safely tolerated single doses up to 18 times the normal dose. Patients should be counselled regarding the risks of liver test abnormalities, gastrointestinal adverse reactions, and fat-soluble vitamin deficiencies. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Maralixibat functions by: Patients with Alagille syndrome experience potentially debilitating pruritus. The exact mechanism of cholestatic pruritus in Alagille syndrome is not well defined, however it is correlated with elevated total serum bile acid concentrations. Enterohepatic circulation involves the synthesis of bile acid from cholesterol in the liver, conjugation with glycine or taurine, excretion into the duodenum, 95% resorption in the distal ileum through the ileal bile acid transporter (IBAT), return to the liver via the portal vein, and uptake into the liver by the sodium-dependent taurocholate co-transporting peptide (NTCP). It is important to note that unconjugated bile acids may freely diffuse across the intestinal mucosa or be transported across by other organic anion transporters. Maralixibat reversibly inhibits IBAT to decrease bile acid resorption in the ileum, leading to decreased resorption of bile acids in the distal ileum, increased elimination of bile acids in the feces, and decreased serum bile acids. The mechanism of action of maralixibat also leads to increased rates of diarrhea in patients. Under normal conditions, bile acids binding to the farnesoid X receptor (FXR) in the liver by via nuclear receptor small heterodimer partner (SHP) or in the ileum via fibroblast growth factor 19 (FGF19), triggers signal cascade that inhibits CYP7A1-mediated bile acid synthesis. Inhibition of IBAT by maralixibat, inhibits these negative feedback loops, leading to increased bile acid synthesis, and a reduction of low density lipoprotein cholesterol. In one clinical trial (NCT02057692), not all dose strengths were associated with a clinically significant difference between maralixibat and placebo. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Categories:

Maralixibat is categorized under the following therapeutic classes: Alimentary Tract and Metabolism, Bile and Liver Therapy, Bile Therapy, Cytochrome P-450 CYP3A Inhibitors, Cytochrome P-450 CYP3A4 Inhibitors, Cytochrome P-450 CYP3A4 Inhibitors (weak), Cytochrome P-450 Enzyme Inhibitors, Ileal bile acid transport inhibitor, Ileal Bile Acid Transporter Inhibitor, Organic Anion Transporting Polypeptide 2B1 Inhibitors. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.