Maralixibat

Identification

Summary

Maralixibat is an ileal bile acid transporter inhibitor indicated to treat cholestatic pruritus in patients with Alagille syndrome.

Brand Names

Livmarli

Generic Name

Maralixibat

DrugBank Accession Number

DB16226

Background

Maralixibat (also known as SHP625, LUM001, and lopixibat) is an ileal bile acid transporter inhibitor, like odevixibat.^1,2,3 Maralixibat is indicated for the treatment of cholestatic pruritus in patients with Alagille syndrome.³

Previously, patients with cholestatic pruritus associated with Alagille syndrome were treated with antihistamines, rifampin, ursodeoxycholic acid, cholestyramine, naltrexone, and sertraline alone or in combination.² 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.² Surgical interventions such as partial external bile diversion and ileal exclusion have also been used as treatments.²

Maralixibat represents the first FDA-approved treatment for cholestatic pruritus in patients with Alagille syndrome. It was granted FDA approval on 29 September 2021.³ 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:⁴ it was granted marketing authorization in Europe on 13 December 2022.⁶ On July 21, 2023, maralixibat was also approved by Health Canada.⁷

Type

Small Molecule

Groups

Approved, Investigational

Structure

3D

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MOLSDF3D-SDFPDBSMILESInChI

Similar Structures

Structure for Maralixibat (DB16226)

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Weight

Average: 674.96
Monoisotopic: 674.398604889

Chemical Formula

C₄₀H₅₆N₃O₄S

Synonyms

• Lopixibat
• Lopixibat cation
• Maralixibat
• Maralixibat cation

External IDs

• LUM-001 cation
• LUM001 cation

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Pharmacology

Indication

Maralixibat is indicated in the treatment of cholestatic pruritus in patients with Alagille syndrome.³ This indication is approved for use in patients at least one month old in the US ³ and at least two months old in Europe.⁵ In Canada, it is reserved for use in adults.⁷

In the US, maralixibat is also indicated for the treatment of cholestatic pruritus in patients 5 years of age and older with progressive familial intrahepatic cholestasis (PFIC).⁹

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Associated Conditions

Indication Type	Indication	Combined Product Details	Approval Level	Age Group	Patient Characteristics	Dose Form
Treatment of	Cholestatic pruritus		••••••••••••	••••••••••• •••••• •••••••••		••••••••
Treatment of	Cholestatic pruritus		••••••••••••			••••••••
Treatment of	Cholestatic pruritus		••••••••••••			••••••••
Treatment of	Cholestatic pruritus		••••••••••••			••••••••

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Pharmacodynamics

Maralixibat is indicated in the treatment of cholestatic pruritus in patients with Alagille syndrome who are at least 1 year old.³ 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.³ Patients should be counselled regarding the risks of liver test abnormalities, gastrointestinal adverse reactions, and fat-soluble vitamin deficiencies.³

Mechanism of action

Patients with Alagille syndrome experience potentially debilitating pruritus.³ The exact mechanism of cholestatic pruritus in Alagille syndrome is not well defined, however it is correlated with elevated total serum bile acid concentrations.^2,3

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).¹ 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.¹

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.^1,3 The mechanism of action of maralixibat also leads to increased rates of diarrhea in patients.¹

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.¹ Inhibition of IBAT by maralixibat, inhibits these negative feedback loops, leading to increased bile acid synthesis, and a reduction of low density lipoprotein cholesterol.¹

In one clinical trial (NCT02057692), not all dose strengths were associated with a clinically significant difference between maralixibat and placebo.²

Target	Actions	Organism
AIleal sodium/bile acid cotransporter	inhibitor	Humans

Absorption

Following single oral administration of maralixibat in healthy adults at doses ranging from 1 mg to 500 mg, plasma concentrations of maralixibat were below the limit of quantification (0.25 ng/mL) at doses less than 20 mg and PK parameters could not be reliably estimated.⁸

Following a single dose administration of 30 mg under fasted conditions, median T_max was 0.75 and mean (SD) C_max and AUC_last were 1.65 (1.10) ng/ml and 3.43 (2.13) ng·h/mL, respectively.⁸

Maralixibat is minimally absorbed and plasma concentrations are often below the limit of quantification (0.25 ng/mL) after single or multiple doses at recommended doses. Following a single oral administration of maralixibat 30, 45, and 100 mg liquid formulation under fasted conditions, AUC_last and C_max increased in a dose-dependent manner with increases of 4.6-and 2.4-fold, respectively, following a 3.3-fold dose increase from 30 to 100 mg.⁸

No accumulation of maralixibat was observed following repeated oral administration of maralixibat in healthy adults at doses up to 100 mg once daily.⁸

Concomitant administration of a high-fat meal with a single oral dose of maralixibat decreased both the rate and extent of absorption. AUC and C_max of maralixibat values in the fed state were 64.8% to 85.8% lower relative to oral administration of 30 mg in fasted conditions. The effect of food on the changes of systemic exposures to maralixibat is not clinically significant.⁸

Volume of distribution

Not Available

Protein binding

Maralixibat is 91% bound to plasma proteins in vitro.³

Metabolism

No maralixibat metabolites have been detected in plasma. Three minor metabolites, accounting for <3% of maralixibat-associated fecal radioactivity in total, were identified following oral administration of [¹⁴C]maralixibat.⁸ The structures of these metabolites have not been defined in the literature.

Route of elimination

Fecal excretion was found to be the major route of elimination. Following a single oral dose of 5 mg ¹⁴C-maralixibat, 73% of the dose was excreted in the feces with 0.066% in the urine. 94% of the fecal excretion was as unchanged maralixibat.⁸

Half-life

The mean half life of maralixibat is 1.6 hours.³

Clearance

Not Available

Adverse Effects

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Toxicity

Data regarding overdoses are rare, given that patients have tolerated single doses up to 500 mg.³ In the event of an overdose, discontinue maralixibat and initiate symptomatic and supportive treatment.³

Maralixibat oral solution contains 364.5 mg/mL propylene glycol.³ Patients aged 1 month to <5 years can safely tolerate up to 50 mg/kg/day of propylene glycol.³ Patients experiencing an overdose of propylene glycol may present with CNS, cardiovascular, or respiratory effect, as well as hyperosmolality.³ Symptoms of propylene glycol overdose may resolve as it is eliminated from the body.³

Pathways

Not Available

Pharmacogenomic Effects/ADRs

Not Available

Interactions

Drug Interactions

This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
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Asunaprevir	The therapeutic efficacy of Asunaprevir can be decreased when used in combination with Maralixibat.
Atorvastatin	The therapeutic efficacy of Atorvastatin can be decreased when used in combination with Maralixibat.
Cholestyramine	The therapeutic efficacy of Maralixibat can be decreased when used in combination with Cholestyramine.
Colesevelam	The therapeutic efficacy of Maralixibat can be decreased when used in combination with Colesevelam.
Colestipol	The therapeutic efficacy of Maralixibat can be decreased when used in combination with Colestipol.

Food Interactions

• Take with or without food. Administration with a high-fat meal decreases the rate and extent of absorption, but not to a clinically significant degree.

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Product Ingredients

Ingredient	UNII	CAS	InChI Key
Maralixibat chloride	V78M04F0XC	228113-66-4	POMVPJBWDDJCMP-RUKDTIIFSA-M

International/Other Brands

Livmarli (Mirum Pharmaceuticals, Inc.)

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Livmarli	Solution	9.5 mg / mL	Oral	Mirum Pharmaceuticals, Inc.	2023-08-11	Not applicable
Livmarli	Solution	9.5 mg/1mL	Oral	Mirum Pharmaceuticals Inc.	2021-09-29	Not applicable
Livmarli	Solution	9.5 mg/ml	Oral	Mirum Pharmaceuticals International B.V.	2023-02-08	Not applicable

Categories

ATC Codes

A05AX04 — Maralixibat chloride

• A05AX — Other drugs for bile therapy
• A05A — BILE THERAPY
• A05 — BILE AND LIVER THERAPY
• A — ALIMENTARY TRACT AND METABOLISM

Drug Categories

• 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
• Heterocyclic Compounds, Fused-Ring
• Ileal bile acid transport inhibitor
• Ileal Bile Acid Transporter Inhibitor
• Organic Anion Transporting Polypeptide 2B1 Inhibitors
• Sulfur Compounds

Classification

Not classified

Affected organisms

Not Available

Chemical Identifiers

UNII

UYB6UOF69L

CAS number

716313-53-0

InChI Key

STPKWKPURVSAJF-LJEWAXOPSA-N

InChI

InChI=1S/C40H56N3O4S/c1-5-7-19-40(20-8-6-2)30-48(45,46)37-18-15-34(41(3)4)27-36(37)38(39(40)44)33-13-16-35(17-14-33)47-29-32-11-9-31(10-12-32)28-43-24-21-42(22-25-43)23-26-43/h9-18,27,38-39,44H,5-8,19-26,28-30H2,1-4H3/q+1/t38-,39-/m1/s1

IUPAC Name

1-{[4-({4-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1lambda6-benzothiepin-5-yl]phenoxy}methyl)phenyl]methyl}-1,4-diazabicyclo[2.2.2]octan-1-ium

SMILES

CCCCC1(CCCC)CS(=O)(=O)C2=CC=C(C=C2[C@H]([C@H]1O)C1=CC=C(OCC2=CC=C(C[N+]34CCN(CC3)CC4)C=C2)C=C1)N(C)C

References

General References

1. Al-Dury S, Marschall HU: Ileal Bile Acid Transporter Inhibition for the Treatment of Chronic Constipation, Cholestatic Pruritus, and NASH. Front Pharmacol. 2018 Aug 21;9:931. doi: 10.3389/fphar.2018.00931. eCollection 2018. [Article]
2. Shneider BL, Spino C, Kamath BM, Magee JC, Bass LM, Setchell KD, Miethke A, Molleston JP, Mack CL, Squires RH, Murray KF, Loomes KM, Rosenthal P, Karpen SJ, Leung DH, Guthery SL, Thomas D, Sherker AH, Sokol RJ: Placebo-Controlled Randomized Trial of an Intestinal Bile Salt Transport Inhibitor for Pruritus in Alagille Syndrome. Hepatol Commun. 2018 Sep 24;2(10):1184-1198. doi: 10.1002/hep4.1244. eCollection 2018 Oct. [Article]
3. FDA Approved Drug Products: Livmarli (Marilixibat) Oral Solution [Link]
4. EMA Summary of Opinion: Livmarli (maralixibat chloride) [Link]
5. EMA Approved Drug Products: Livmarli (maralixibat) Oral Solution [Link]
6. Business Wire: Mirum Pharmaceuticals’ LIVMARLI (maralixibat) Approved by the European Commission for the Treatment of Cholestatic Pruritus in Patients with Alagille Syndrome Two Months and Older [Link]
7. Health Canada Approved Drug Products: LIVMARLI (Maralixibat) Oral Solution [Link]
8. FDA Approved Drug Products: LIVMARLI® (maralixibat) oral solution (September 2023) [Link]
9. FDA Approved Drug Products LIVMARLI (maralixibat) oral solution (March 2024) [Link]

External Links

ChemSpider

8007375

BindingDB

50140282

RxNav

2571074

ChEMBL

CHEMBL363392

PharmGKB

PA166268803

Wikipedia

Maralixibat_chloride

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
3	Active Not Recruiting	Treatment	Alagille Syndrome	1
3	Active Not Recruiting	Treatment	Progressive Familial Intrahepatic Cholestasis (PFIC)	2
3	Completed	Treatment	Progressive Familial Intrahepatic Cholestasis (PFIC)	1
3	Withdrawn	Treatment	Progressive Familial Intrahepatic Cholestasis (PFIC)	1
2	Active Not Recruiting	Treatment	Alagille Syndrome / Cholestatic Liver Disease / Progressive Familial Intrahepatic Cholestasis (PFIC)	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Solution	Oral	9.5 mg/mL
Solution	Oral	9.5 mg / mL
Solution	Oral	9.5 mg/1mL

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
US11260053	No	2011-05-26	2031-05-26
US11229647	No	2020-02-12	2040-02-12
US11376251	No	2012-10-26	2032-10-26
US11497745	No	2020-02-12	2040-02-12

Properties

State

Liquid

Experimental Properties

Not Available

Predicted Properties

Property	Value	Source
Water Solubility	2.39e-05 mg/mL	ALOGPS
logP	3.96	ALOGPS
logP	2.7	Chemaxon
logS	-7.5	ALOGPS
pKa (Strongest Acidic)	14.15	Chemaxon
pKa (Strongest Basic)	5.68	Chemaxon
Physiological Charge	1	Chemaxon
Hydrogen Acceptor Count	6	Chemaxon
Hydrogen Donor Count	1	Chemaxon
Polar Surface Area	70.08 Å2	Chemaxon
Rotatable Bond Count	13	Chemaxon
Refractivity	209.09 m3·mol-1	Chemaxon
Polarizability	78.83 Å3	Chemaxon
Number of Rings	6	Chemaxon
Bioavailability	0	Chemaxon
Rule of Five	No	Chemaxon
Ghose Filter	No	Chemaxon
Veber's Rule	No	Chemaxon
MDDR-like Rule	Yes	Chemaxon

Predicted ADMET Features

Not Available

Spectra

Mass Spec (NIST)

Not Available

Spectra

Not Available

Chromatographic Properties

Collision Cross Sections (CCS)

Not Available

Targets

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Details1. Ileal sodium/bile acid cotransporter

Kind

Protein

Organism

Humans

Pharmacological action

Yes

Actions

Inhibitor

General Function

Bile acid:sodium symporter activity

Specific Function

Plays a critical role in the sodium-dependent reabsorption of bile acids from the lumen of the small intestine. Plays a key role in cholesterol metabolism.

Gene Name

SLC10A2

Uniprot ID

Q12908

Uniprot Name

Ileal sodium/bile acid cotransporter

Molecular Weight

37713.405 Da

References

1. Karpen SJ, Kelly D, Mack C, Stein P: Ileal bile acid transporter inhibition as an anticholestatic therapeutic target in biliary atresia and other cholestatic disorders. Hepatol Int. 2020 Sep;14(5):677-689. doi: 10.1007/s12072-020-10070-w. Epub 2020 Jul 11. [Article]
2. FDA Approved Drug Products: Livmarli (Marilixibat) Oral Solution [Link]

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Drug created at December 15, 2020 18:16 / Updated at April 08, 2024 21:18