Maralixibat (Monograph)

Brand name: Livmarli
Drug class: GI Drugs, Miscellaneous
Chemical name: (4R,5R)-5-[4-[[4-(4-aza-1-azoniabicyclo[2.2.2]octan-1-ylmethyl)phenyl]methoxy]phenyl]-3,3-dibutyl-7-(dimethylamino)-1,1-dioxo-4,5-dihydro-2H-1lambda6-benzothiepin-4-ol
Molecular formula: C₄₀H₅₆N₃O₄S+
CAS number: 716313-53-0

Medically reviewed by Drugs.com on Sep 21, 2022. Written by ASHP.

Introduction

Ileal bile acid transporter (IBAT) inhibitor.

Uses for Maralixibat

Cholestatic Pruritus in Alagille Syndrome

Treatment of cholestatic pruritus associated with Alagille syndrome (ALGS) in patients ≥1 year of age. Designated an orphan drug by FDA for use in this condition.

ALGS is an autosomal dominant, multisystem disorder caused by various mutations affecting the Notch signaling pathway. The syndrome, which is usually diagnosed in infancy, mainly affects the liver and is associated with significant cholestasis. Patients often suffer from intractable pruritus. Some drugs have been used for symptomatic treatment (e.g., ursodiol, cholestyramine, rifampin, colesevelam, antihistamines). Maralixibat may provide an additional option.

Maralixibat Dosage and Administration

General

Pretreatment Screening

Assess baseline liver function (e.g., ALT, AST, total bilirubin, direct bilirubin, INR) to establish a baseline pattern of variability prior to initiation of therapy.
Obtain fat-soluble vitamin (e.g., vitamins A, D, E, and K [measured using INR levels]) serum levels at baseline; initiate vitamin supplementation if a deficiency is diagnosed.

Patient Monitoring

Monitor for the development of liver-related adverse reactions during therapy.
Monitor liver function (e.g., ALT, AST, total bilirubin, direct bilirubin, INR) during therapy.
Monitor for fat-soluble vitamin deficiency (e.g., vitamins A, D, E, and K [measured using INR levels]) during therapy; initiate vitamin supplementation if a deficiency is diagnosed.
Monitor for the development of adverse GI effects during treatment.

Administration

Oral Administration

Administer orally as a solution.

Administer oral solution approximately 30 minutes before the first meal of the day using provided calibrated measuring device (0.5 mL, 1 mL, or 3 mL oral dispenser).

If a dose is missed, take the missed dose as soon as possible within 12 hours of the time it is usually taken, and then resume normal dosing schedule. If the dose is missed by >12 hours, skip the missed dose and take next dose at regularly scheduled time.

Administer maralixibat at least 4 hours before or after administration of bile acid sequestrants.

Dosage

Available as maralixibat chloride; dosage expressed in terms of maralixibat. Commercially available as an oral solution containing 9.5 mg of maralixibat per mL.

Pediatric Patients

Cholestatic Pruritus in Alagille Syndrome

Oral

Age ≥1 year: Initially, 190 mcg/kg once daily for one week, then increase dosage to 380 mcg/kg once daily, as tolerated.

For patients who weigh >70 kg, the maximum daily dose volume is 3 mL or 28.5 mg per day.

Individual dose volumes by patient weight are described in Table 1.

Table 1. Individual Dose Volume of Maralixibat by Patient Weight.1
Patient Weight (kg)	Dosage = 190 mcg/kg Once Daily	Dosage = 380 mcg/kg Once Daily
	Daily dose volume (mL)	Daily dose volume (mL)
5–6	0.1 mL	0.2 mL
7–9	0.15 mL	0.3 mL
10–12	0.2 mL	0.45 mL
13–15	0.3 mL	0.6 mL
16–19	0.35 mL	0.7 mL
20–24	0.45 mL	0.9 mL
25–29	0.5 mL	1 mL
30–34	0.6 mL	1.25 mL
35–39	0.7 mL	1.5 mL
40–49	0.9 mL	1.75 mL
50–59	1 mL	2.25 mL
60–69	1.25 mL	2.5 mL
≥70	1.5 mL	3 mL

Adults

Cholestatic Pruritus in Alagille Syndrome

Oral

Initially, 190 mcg/kg once daily for one week, then increase dosage to 380 mcg/kg once daily, as tolerated.

For patients who weigh >70 kg, the maximum daily dose volume is 3 mL or 28.5 mg per day.

Individual dose volumes by patient weight are described in Table 2.

Table 2. Individual Dose Volume of Maralixibat by Patient Weight.1
Patient Weight (kg)	Dosage = 190 mcg/kg Once Daily	Dosage = 380 mcg/kg Once Daily
	Daily dose volume (mL)	Daily dose volume (mL)
5–6	0.1 mL	0.2 mL
7–9	0.15 mL	0.3 mL
10–12	0.2 mL	0.45 mL
13–15	0.3 mL	0.6 mL
16–19	0.35 mL	0.7 mL
20–24	0.45 mL	0.9 mL
25–29	0.5 mL	1 mL
30–34	0.6 mL	1.25 mL
35–39	0.7 mL	1.5 mL
40–49	0.9 mL	1.75 mL
50–59	1 mL	2.25 mL
60–69	1.25 mL	2.5 mL
≥70	1.5 mL	3 mL

Dosage Modification for Toxicity

Hepatotoxicity

If new onset liver abnormalities occur without other etiology, interrupt maralixibat therapy. When laboratory values stabilize or return to baseline, consider resuming maralixibat at a reduced dosage of 190 mcg/kg once daily, and then increase to 380 mcg/kg once daily, as tolerated. If liver function abnormalities persist or recur or clinical symptoms of hepatitis occur, consider permanently discontinuing therapy.

Permanently discontinue drug if hepatic decompensation occurs (e.g., variceal hemorrhage, ascites, hepatic encephalopathy).

GI Effects

If adverse GI effects (e.g., diarrhea, abdominal pain, vomiting) occur, consider reducing the dose of maralixibat or temporarily withholding therapy. If diarrhea persists or is accompanied by bloody stool, vomiting, dehydration requiring treatment, or fever, consider temporarily withholding therapy.

When diarrhea, abdominal pain, and/or vomiting resolve, resume maralixibat at a reduced dosage of 190 mcg/kg once daily, followed by an increase in dosage, as tolerated. If the adverse GI effect recurs, consider discontinuing the drug.

Prescribing Limits

Pediatric Patients

Cholestatic Pruritus in Alagille Syndrome

Oral

For patients who weigh >70 kg: Maximum daily dose volume is 3 mL or 28.5 mg per day.

Adults

Cholestatic Pruritus in Alagille Syndrome

Oral

For patients who weigh >70 kg: Maximum daily dose volume is 3 mL or 28.5 mg per day.

Special Populations

Hepatic Impairment

No specific dosage recommendations.

If liver abnormalities occur during therapy with maralixibat and no other etiology is identified, consider reducing the dosage of maralixibat or temporarily interrupting therapy.

Renal Impairment

No specific dosage recommendations for patients with renal impairment, including those with end-stage renal disease (ESRD) and those receiving hemodialysis.

Geriatric Patients

No specific dosage recommendations.

Cautions for Maralixibat

Contraindications

None.

Warnings/Precautions

Hepatotoxicity

New or worsening elevations of liver function tests observed during therapy. Most common abnormalities include elevations in ALT, AST, or total bilirubin/direct bilirubin.

Not evaluated in patients with Alagille syndrome and concomitant cirrhosis.

Monitor patients during therapy for elevations in liver tests and for development of liver-related adverse effects. Weigh potential risks against benefits of continuing therapy in patients who experience persistent or recurrent liver function test abnormalities. Permanently discontinue maralixibat if a patient develops portal hypertension or experiences a hepatic decompensation event.

Obtain liver function values at baseline and during therapy. Consider dosage reduction or treatment interruption if abnormalities occur in the absence of other etiology. For persistent or recurrent liver function abnormalities, consider discontinuing therapy.

GI Adverse Effects

Most common adverse GI effects are diarrhea, abdominal pain, and vomiting.

If diarrhea, abdominal pain, and/or vomiting occur with no other etiology, consider reducing dosage of maralixibat or interrupting therapy. Monitor for dehydration and treat promptly.

If diarrhea persists or is accompanied by bloody stool, vomiting, dehydration requiring treatment, or fever, consider temporarily withholding therapy.

Fat-soluble Vitamin Deficiency

Patients with Alagille syndrome can be fat-soluble vitamin-deficient (e.g., vitamins A, D, E, and K) at baseline, and maralixibat may inhibit absorption of these enzymes.

Assess fat-soluble vitamin levels (e.g. vitamins A, D, E, and K [measured using INR levels]) prior to initiation of therapy and during therapy; supplement fat-soluble vitamins if a deficiency is diagnosed.

Consider discontinuing maralixibat if fat-soluble vitamin deficiency persists or worsens despite adequate supplementation.

Specific Populations

Pregnancy

Not expected to result in measurable fetal exposure. No developmental effects observed in animal studies.

Increased supplementation of fat-soluble vitamins may be necessary during pregnancy.

Lactation

Breast-feeding is not expected to result in exposure of the infant to maralixibat at the recommended dosage. Not known whether maralixibat is distributed into human milk. Effects of the drug on breast-fed infants or on milk production also unknown.

Consider developmental and health benefits of breast-feeding along with the mother's need for maralixibat and any potential adverse effects on the breast-fed infant from the drug or underlying maternal condition.

Monitor fat-soluble vitamin levels and provide supplementation if a deficiency is diagnosed during lactation.

Pediatric Use

Safety and efficacy established in 31 patients 1–15 years of age. Additional safety information obtained from 4 studies in 55 patients up to 21 years of age.

Safety and efficacy not established in patients <1 year of age.

Geriatric Use

Safety and efficacy not established in patients ≥65 years of age.

Hepatic Impairment

Clinical studies included patients with Alagille syndrome and hepatic impairment at baseline.

Safety and efficacy not established in patients with Alagille syndrome and clinically significant portal hypertension or decompensated cirrhosis.

Renal Impairment

Pharmacokinetics not studied in patients with renal impairment, including those with end-stage renal disease (ESRD) and those receiving hemodialysis.

Common Adverse Effects

Adverse reactions (≥5%): diarrhea, abdominal pain, vomiting, nausea, fat-soluble vitamin deficiency, liver test abnormalities, GI bleeding, bone fractures.

Interactions for Maralixibat

In vitro, does not induce CYP isoenzymes 1A2, 2B6, or 3A4, or inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, or 2D6 at clinically relevant concentrations. Inhibits CYP3A4 in vitro; however, clinically important pharmacokinetic interactions with CYP3A4 substrates unlikely.

In vitro, does not inhibit P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporter (OAT) 1, OAT3, organic anion transporting polypeptide (OATP) 1B1, OATP1B3, peptide transporter (PEPT) 1, organic cation transporter (OCT) 1, OCT2, OCT3, OCTN1, OCTN2, multidrug resistance protein (MRP) 2, multidrug and toxin extrusion (MATE) 1, or MATE2-K at clinically relevant concentrations. In vitro, inhibits OATP2B1, which can result in decreased absorption of drugs requiring OATP2B1-mediated uptake in the GI tract.

Not a substrate of P-gp, BCRP, OATP1B1, OATP1B3, or OATP2B2; therefore, concomitant therapy with drugs affecting these drug transporters are not expected to affect the pharmacokinetics of maralixibat.

Specific Drugs

Drug

Interaction

Comments

Bile acid sequestrants (e.g., cholestyramine, colesevelam, colestipol)

May reduce absorption and efficacy of maralixibat

Administer maralixibat ≥4 hours before or after administration of the bile acid sequestrant

HMG-CoA reductase inhibitors (statins)

Atorvastatin (OATP2B1 substrate): No clinically relevant effect on atorvastatin pharmacokinetics following concomitant administration with maralixibat 4.75 mg

Lovastatin (OATP2B1 substrate): No clinically relevant effect on lovastatin pharmacokinetics following concomitant administration with maralixibat 4.75 mg once daily

Simvastatin (OATP2B1 substrate): No clinically relevant effect on simvastatin pharmacokinetics following concomitant administration with maralixibat 4.75 mg once daily

Consider monitoring effects of OATP2B1 substrate as needed

Maralixibat Pharmacokinetics

Absorption

Bioavailability

Median time to peak plasma concentration was 0.75 hours following oral administration.

Systemic exposure is minimal. Following oral administration, plasma concentrations are below the limit of quantification in pediatric patients with Alagille syndrome and healthy adults.

Systemic exposure increases in a dose-dependent manner over an oral dose range of 30–100 mg.

No accumulation observed following repeated oral administration of up to 100 mg daily in healthy adults.

Food

High-fat meal decreased total exposure and peak plasma concentrations by 64.8% and 85.8%, respectively, compared with administration in the fasting state.

Distribution

Extent

Not known whether distributed into human milk; however, drug is minimally absorbed following oral administration.

Plasma Protein Binding

91%.

Elimination

Metabolism

No metabolites detected in plasma. Three minor metabolites detected in feces following oral administration.

Elimination Route

Eliminated in feces (73%; 94% as unchanged drug) and urine (0.066%).

Half-life

1.6 hours in healthy adults.

Stability

Storage

Oral

Solution

Store at 20–25°C (excursions permitted between 15–30°C). Discard any remaining maralixibat solution 45 days after first opening of the bottle.

Actions

Reversible inhibitor of the ileal bile acid transporter (IBAT).
Decreases reabsorption of bile acids (primarily the salt forms) from terminal ileum.
Mechanism of action in patients with pruritus associated with Alagille syndrome not fully elucidated, but may involve inhibition of IBAT.
Inhibition of IBAT decreases reuptake of bile salts.

Advice to Patients

Abdominal pain, vomiting, nausea, diarrhea, and dehydration have been reported with the use of maralixibat. Advise patients to contact their healthcare provider if they experience new onset or worsening of these GI adverse events.
Elevations in liver tests (e.g., AST, ALT, total bilirubin) have been observed with use of maralixibat. Advise patients that their healthcare provider will obtain liver tests before starting the drug and periodically during treatment. Advise patients to report any symptoms of liver problems (e.g., nausea, vomiting, skin or the whites of eyes turning yellow, dark or brown urine, pain on the right side of the abdomen, loss of appetite).
Maralixibat may impair absorption of fat-soluble vitamins. Such deficiencies, which include vitamins A, D, E and K, have been reported in some patients during treatment with the drug. Advise patients that their healthcare provider will obtain serum levels of vitamins A, D, E, and INR (for vitamin K) before starting and periodically during treatment to assess for worsening of vitamin deficiency.
Take maralixibat approximately 30 minutes before the first meal of the day using a calibrated measuring device (0.5 mL, 1 mL or 3 mL oral dispenser) provided by the pharmacist to measure and deliver the prescribed dose accurately.
Discard any remaining drug 45 days after first opening of bottle.
Patients taking bile acid binding resins should take maralixibat at least 4 hours before or 4 hours after the bile acid binding resin.
Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.
Advise women to inform their clinician if they are or plan to become pregnant or plan to breast-feed.
Inform patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Maralixibat can only be obtained through a designated specialty pharmacy. Contact the manufacturer or consult the Livmarli website for specific availability information.