Maralixibat for Cholestatic Pruritus: A Comprehensive Drug Review

Overview:

The second rare liver disease indication for the ileal bile acid transporter (IBAT) inhibitor is now approved by the U.S. (United States) Food and Drug Administration (FDA) for the treatment of cholestatic pruritus in patients five years of age or older with progressive familial intrahepatic cholestasis (PFIC). On July 20, 2021, the FDA authorized Maralixibat to manage cholestatic pruritus in individuals with Alagille syndrome.

Drug Group:

Maralixibat is a member of the ileal bile acid transporter (IBAT) inhibitors, a relatively new family of medications.

Available Doses and Dosage Forms:

Maralixibat comes in only one dose form.

• Oral solution of Maralixibat 9.5 mg/mL (milligrams per milliliter).

For Patients:

What Is Cholestatic Pruritus?

An excruciating and persistent itching sensation known as cholestatic pruritus is linked to several cholestatic liver disorders. In addition to substantially lowering a patient's quality of life, it can cause sleep disorders and psychological discomfort. A newly licensed drug called Maralixibat provides a unique and focused method of treating this illness in particular patient groups.

• Pathophysiology: To help with fat digestion, the liver secretes bile, a digestive fluid, into the small intestine in healthy people. The essential elements of bile acids are then taken up again by the gut and recycled back into the liver. However, poor bile flow causes this enterohepatic circulation of bile acids to be disturbed in cholestatic liver disorders. Cholestasis is the resultant accumulation of bile acids in the circulation. Cholestatic pruritus is thought to be primarily caused by an excess of bile acids. These hydrophilic molecules can settle on the skin, irritating nerve endings and causing excruciating, continuous itching. The itching frequently worsens at night, worsening sleep quality and general well-being.

How Does Maralixibat Work?

Maralixibat is a member of a recently developed class of drugs called ileal bile acid transporter (IBAT) inhibitors. It functions by selectively attacking the IBAT protein, which is found in the small intestine's terminal ileum. As a transporter, IBAT helps bile acids become reabsorbed from the gut lumen and back into circulation.

Maralixibat efficiently prevents this reabsorption process by attaching to IBAT. As a result, a larger percentage of bile acids are eliminated in the stool, which lowers the amount of bile acids in circulation. It is thought that Maralixibat primarily relieves cholestatic pruritus by reducing exposure to systemic bile acid.

What Is the Dosage of Maralixibat?

• It is advised to take 380 mcg/kg (micrograms per kilogram) once a day, half an hour before the day's first meal.

• The recommended first oral dosage is 190 mcg/kg once daily; if tolerated, this should be raised to 380 mcg/kg once daily after a week.

How Effective Is Maralixibat?

Maralixibat has shown encouraging outcomes in clinical studies for lowering pruritus intensity in individuals with progressive familial intrahepatic cholestasis (PFIC) and cholestatic pruritus linked to Alagille syndrome. But it is crucial to remember that:

• Symptomatic Relief: Maralixibat treats itching, one of the main symptoms, but it does not treat the underlying liver condition.

• Emerging Therapy: To assess its effectiveness in a larger group of people with cholestatic pruritus, more studies may be required as long-term safety data are currently being gathered.

• Tailored Approach: A medical expert ascertains the ideal dosage of Maralixibat by considering the patient's weight and tolerance. Seeking advice from a medical professional is crucial to determine whether Maralixibat is appropriate for each patient and thoroughly review the possible advantages and disadvantages.

What Are the Things to Inform the Doctor Before Taking the Drug?

To maximize the therapeutic effect of Maralixibat while reducing possible hazards, it is necessary to provide comprehensive details regarding the following:

• Comprehensive Medical History: To find any underlying illnesses, such as comorbid liver diseases, intestinal issues, or recognized allergies, a thorough medical history is required. It is also essential to disclose previous operations and current prescription and over-the-counter medication usage to assess possible interactions and direct treatment choices.

• Pregnancy and Lactation: Patients who are female and have the potential to become pregnant should be made aware of the paucity of information on the safety of Maralixibat throughout these stages. A risk-benefit analysis is crucial, and if nursing is continuing strong or if the pregnancy is known or planned, other therapeutic alternatives might be considered.

• Baseline Laboratory Testing: Before starting Maralixibat medication, a laboratory assessment of liver function and general health may be advised. This baseline evaluation offers a point of reference for keeping an eye out for any changes that may occur throughout therapy.

How Is Maralixibat Administered?

• Maralixibat is taken orally as a solution, and dosage is customized according to patient weight and tolerance.

• Usually, a single daily dosage is advised, either with or without meals.

• Take Maralixibat at least four hours before or four hours after taking a bile acid-binding resin if one is a patient on these medications.

• The pharmacy will supply a calibrated measurement tool (an oral dosing dispenser, either 0.5 mL, one mL, or three mL) to precisely measure and administer the recommended dosage.

What Are the Side Effects of Maralixibat?

The following is a classification of frequent and severe side effects:

Common Side Effects:

1. Gastrointestinal Disorders: It is common to hear reports of gastrointestinal issues, such as vomiting, diarrhea, and stomach discomfort. These are normally manageable, but if they worsen or continue, it is advisable to contact the prescriber right away.

2. Possible Nutrient Deficiencies: The way Maralixibat works can reduce the way fat-soluble vitamins (A, D, E, and K) are absorbed. To treat any deficiencies and guarantee appropriate nutritional balance, prescribers may advise vitamin supplementation.

Severe Side Effects Needing Emergency Medical Attention:

1. Severe Gastrointestinal Events: To rule out any problems, persistent or severe diarrhea, especially when there is blood in the stool, requires prompt medical attention.

2. Hepatic Dysfunction: Lack of appetite, stomach discomfort, jaundice (yellowing of the skin or eyes), and dark urine.

3. Elevated Bone Fracture Risk: Maralixibat has been linked to an elevated risk of fractures, notwithstanding its rarity. Reporting any bone pain or fractures to the prescriber can help them assess the situation.

4. Allergic Reactions: Breathing difficulties, hives, or facial, oral, or lingual edema.

Dietary Considerations:

Although there are not many well-established dietary recommendations connected to Maralixibat, the following basic advice may be useful:

• Manage Digestive Issues: If having diarrhea, starting with a bland, low-fat, low-fiber, and low-spice diet may help.

• Treat Nutrient Deficiencies: Consult the physician about adding meals high in vitamins A, D, E, and K or taking supplements to make up for lower absorption.

• Be Hydrated and Eat a Balanced Diet: To promote general health, be hydrated and strive for a diet rich in fruits, vegetables, whole grains, and lean protein.

Missed Dose:

If a dosage is missed, the normal dosing plan should be continued, and the missing dose should be given as soon as possible, preferably within 12 hours of the scheduled time. A missed dosage can be skipped, and the regular dosing plan can be continued if it is more than 12 hours away.

Overdose:

• When compared to lower dosages, single doses of Maralixibat up to 500 mg (roughly 18 times the therapeutic dose) were well tolerated by healthy people and did not significantly increase the number of side events. In the event of an overdose, stop taking Maralixibat, keep an eye out for any symptoms, and, if necessary, take general supportive action.

• Propylene glycol (364.5 mg/mL) is an excipient in Maralixibat. It is widely accepted that oral dosages of propylene glycol up to 50 mg/kg/day (one month to < 5 years of age) and 500 mg/kg/day (≥ five years of age) are safe.

• Propylene glycol overdoses can cause hyperosmolality (it is a disorder where there is an excessive amount of salt (sodium), glucose, and other compounds in the blood) and neurological, cardiovascular, or respiratory symptoms. These adverse effects can go away when the propylene glycol is eliminated.

Storage:

• Keep at 20 to 25 degrees Celsius (68 to 77 degrees Fahrenheit), with a maximum deviation of 15 to 30 degrees Celsius (59 to 86 degrees Fahrenheit) allowed.

• After 45 days following the first bottle opening, dispose of any leftover Maralixibat.

• Always keep bottles with their caps on.

For Doctors:

Indications:

• Patients with Alagille syndrome (ALGS) who are one year of age or older benefit from therapy for cholestatic pruritus with Maralixibat, an ileal bile acid transporter (IBAT) inhibitor.

• It is also useful in a collection of hereditary conditions known as progressive familial intrahepatic cholestasis (PFIC), which impacts the movement of bile through the liver.

Dose:

There is just one dosing type for Maralixibat:

• Oral Solution: There are 9.5 mg of Maralixibat per milliliter (mL) in this solution.

Dosing Considerations:

A medical specialist will establish the precise dosage of Maralixibat depending on the patient's weight and tolerance. The following summarizes the main ideas for prescribers:

• Dose Titration: Until the ideal balance between effectiveness and tolerability is reached, Maralixibat treatment usually begins with a low dose and is progressively raised.

• Beginning Dosage: The recommended starting dose is 285 mcg/kg (micrograms per kilogram) given one day.

• Dose Adjustments: Depending on each patient's reaction and tolerance, the healthcare provider may gradually raise the dosage after the first dose, usually doubling it every time.

• Maximum Dosage: Regardless of the patient's weight, a daily dose of 38 mg is the maximum that is advised.

What Are the Pharmacological Aspects of Maralixibat?

• Pharmacodynamics: Maralixibat diminishes the reuptake of bile acid and efficiently prevents this reabsorption process by attaching to IBAT. As a result, a larger percentage of bile acids are eliminated in the stool, which lowers the amount of bile acids in circulation. It is thought that Maralixibat primarily relieves cholestatic pruritus by reducing exposure to systemic bile acid. It is believed that too much bile acid irritates epidermal nerve endings, resulting in excruciating itching. The symptom may be lessened with Maralixibat by lowering bile acid levels.

• Mechanism: Ileal bile acid transporter (IBAT) is a reversible inhibitor of Maralixibat. It reduces the amount of bile acids that are reabsorbed from the terminal ileum, especially the salt forms. One of the most prevalent symptoms in ALGS patients is pruritus, whose pathogenesis is still unclear in these individuals. The exact method by which Maralixibat relieves pruritus in individuals with ALGS is uncertain. However, it may entail inhibiting the IBAT, which lowers bile salt absorption as seen by a drop in blood bile acid.

• Pharmacokinetics:

1. Absorption: Maralixibat is taken orally in the form of a solution. Its absorption from the gastrointestinal system is thought to be inadequate, while its exact nature is unknown.

2. Distribution: Maralixibat's free mobility in circulation is restricted by its strong (over 90 percent) binding to plasma proteins, which may have an impact on how well it reaches its target tissues.

3. Metabolism: The human body's metabolism of Maralixibat is not well understood. Research indicates that there are very few or no Maralixibat metabolites in the blood.

4. Excretion: In healthy people, the mean half-life (t1/2) after a single oral dosage of 30 mg Maralixibat was 1.6 hours. Due to its decreased absorption and possible biliary excretion, Maralixibat is primarily eliminated through feces. 73 percent of the dosage is eliminated by feces, while 0.066 percent is eliminated through urine. 94 percent of the excreted feces remained unaltered.

Toxicity:

Non-Clinical Toxicity:

1. Carcinogenesis: After giving oral Maralixibat chloride to mice at dosages of up to 25 mg/kg/day (for males) or 75 mg/kg/day (for females) for 26 weeks, no drug-related tumors were seen.

2. Mutation: In vitro tests (bacterial reverse mutation, chromosomal aberration in mammalian cells) and in vivo tests (mouse bone marrow micronucleus) yielded negative results for Maralixibat chloride.

3. Deficit in Fertility: Oral administration of up to 2000 mg/kg/day to female rats or 750 mg/kg/day to male rats did not result in any observable effects on fertility.

Clinical Toxicity: The most frequent adverse responses (less than five percent) are bone fractures, gastrointestinal bleeding, diarrhea, vomiting, a lack of fat-soluble vitamins, and abnormal liver tests.

Clinical Studies:

A recent clinical trial examined the efficacy of Maralixibat in mitigating pruritus or itching, in children diagnosed with Alagille syndrome (ALGS). Here is a brief synopsis:

• 31 children who had both ALGS and itching were taken for the clinical trial. All were given Maralixibat for eighteen weeks, following a period of initial dosage adjustment.

• Following that, 29 patients were either kept on Maralixibat or moved to a placebo for four weeks. Compared to a placebo, Maralixibat dramatically decreased itching throughout the 4-week withdrawal phase.

• After quitting Maralixibat, the placebo group's itching ratings went back to baseline.

• After starting Maralixibat, the itching scores of both groups were comparable.

These findings from the clinical trial imply that Maralixibat is useful in helping kids with ALGS manage their itching.

What Are the Contraindications of Maralixibat?

Maralixibat is not appropriate for all individuals. The primary contraindications are as follows:

• Hypersensitivity: The drug should not be taken if allergic to Maralixibat or any of its constituents.

• Pregnancy and Lactation: It is not advised for women to take Maralixibat while they are pregnant or nursing due to the paucity of safety evidence. In these situations, alternative therapy alternatives must be investigated.

Warnings and Precautions:

• Liver Disorders: Get baseline liver tests and keep an eye out for abnormalities while undergoing therapy. If anomalies arise, lowering the dose or stopping the medication may be taken into consideration. It may be wise to stop taking Maralixibat if there are chronic or recurring abnormalities in liver tests.

• Adverse Reactions to the Gastrointestinal System: If a patient has diarrhea that does not go away, stomach discomfort, vomiting, diarrhea that includes blood in the stool, vomiting, fever, or dehydration that has to be treated, think about stopping Maralixibat medication.

• Deficiency in Fat-Soluble Vitamins (FSV): Determine baseline values and track while on therapy. If a deficit is found, add more. If the FSV deficit continues or worsens even with FSV supplementation, one should stop Maralixibat medication.

Drug Interactions of Maralixibat:

• Bile Acid Sequestrants: These cholesterol-lowering drugs may prevent Maralixibat from being absorbed properly. While using Maralixibat, talk to the doctor about other cholesterol-lowering drugs.

• OATP2B1 Substrates: Drugs that function as the OATP2B1 (organic anion transporting polypeptide 2B1) transporter protein's substrates may interact with Maralixibat. Studies on routinely used statins have not revealed any clinically significant interactions, nevertheless. To ensure safe usage of Maralixibat, it is still vital to let the doctor know about all the medications used, both prescription and over-the-counter.

Specific Considerations:

1. Pregnancy and Breastfeeding: It is not advised for women to use Maralixibat when they are pregnant or nursing because of fetal exposure risks. There are possible hazards, even if they are improbable, given poor absorption. Maralixibat may decrease the absorption of vitamins, necessitating their supplementation during pregnancy. Also, there are a few safety studies on the use of Maralixibat during pregnancy and lactation.

2. Children: The safety and efficacy of Maralixibat for children with Alagille syndrome between the ages of one and fifteen have been established.

3. Liver Impairment: Individuals with decompensated cirrhosis or severe portal hypertension may utilize Maralixibat. However, its usage in these individuals should be handled with caution.