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, who are at least 1 year old.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 maralixibat was granted marketing authorization in Europe on 13 December 2022.6

Type
Small Molecule
Groups
Approved, Investigational
Structure
Weight
Average: 674.96
Monoisotopic: 674.398604889
Chemical Formula
C40H56N3O4S
Synonyms
  • Lopixibat
  • Lopixibat cation
  • Maralixibat
  • Maralixibat cation
External IDs
  • LUM-001 cation
  • LUM001 cation

Pharmacology

Indication

Maralixibat is indicated in the treatment of cholestatic pruritus in patients with Alagille syndrome.3 It is approved for use in patients who are at least one year old in the US 3 and two months of age and older in Europe.5

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Associated Conditions
Contraindications & Blackbox Warnings
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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

TargetActionsOrganism
AIleal sodium/bile acid cotransporter
inhibitor
Humans
Absorption

Maralixibat is not extensively absorbed.3 A single 30 mg dose of maralixibat given under fasted conditions reached a median Tmax of 0.75 hours, with a mean Cmax of 1.65 ± 1.10 ng/mL, and a mean AUClast of 3.43 ± 2.13 h*ng/mL.3

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.3

Volume of distribution

Not Available

Protein binding

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

Metabolism

Maralixibat metabolites have not been identified in plasma, however 3 minor metabolites have been recovered in the feces.3 The structure of these metabolites have not been defined in the literature.

Route of elimination

A 5 mg radiolabelled dose of maralixibat is 73% eliminated in feces and 0.066% eliminated in urine.3 94% of the dose recovered in the feces was as the unmetabolized parent compound.3 <3% of the total dose is metabolized.3

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.
DrugInteraction
AsunaprevirThe therapeutic efficacy of Asunaprevir can be decreased when used in combination with Maralixibat.
AtorvastatinThe therapeutic efficacy of Atorvastatin can be decreased when used in combination with Maralixibat.
CholestyramineThe therapeutic efficacy of Maralixibat can be decreased when used in combination with Cholestyramine.
ColesevelamThe therapeutic efficacy of Maralixibat can be decreased when used in combination with Colesevelam.
ColestipolThe therapeutic efficacy of Maralixibat can be decreased when used in combination with Colestipol.
FexofenadineThe therapeutic efficacy of Fexofenadine can be decreased when used in combination with Maralixibat.
MesalazineThe therapeutic efficacy of Mesalazine can be decreased when used in combination with Maralixibat.
PitavastatinThe therapeutic efficacy of Pitavastatin can be decreased when used in combination with Maralixibat.
SevelamerThe therapeutic efficacy of Maralixibat can be decreased when used in combination with Sevelamer.
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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.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Maralixibat chlorideV78M04F0XC228113-66-4POMVPJBWDDJCMP-RUKDTIIFSA-M
International/Other Brands
Livmarli (Mirum Pharmaceuticals, Inc.)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
LivmarliSolution9.5 mg/1mLOralMirum Pharmaceuticals Inc.2021-09-29Not applicableUS flag

Categories

ATC Codes
A05AX04 — Maralixibat chloride
Drug Categories
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]
ChemSpider
8007375
BindingDB
50140282
RxNav
2571074
ChEMBL
CHEMBL363392
PharmGKB
PA166268803
Wikipedia
Maralixibat_chloride

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3CompletedTreatmentProgressive Familial Intrahepatic Cholestasis (PFIC)1
3Enrolling by InvitationTreatmentProgressive Familial Intrahepatic Cholestasis (PFIC)1
3RecruitingTreatmentAlagille Syndrome (ALGS)1
3RecruitingTreatmentProgressive Familial Intrahepatic Cholestasis (PFIC)1
3WithdrawnTreatmentProgressive Familial Intrahepatic Cholestasis (PFIC)1
2Active Not RecruitingTreatmentCholestatic Liver Disease1
2CompletedTreatmentAlagille Syndrome5
2CompletedTreatmentPrimary Bilary Cirrhosis (PBC) / Primary Biliary Cholangitis1
2CompletedTreatmentPrimary Sclerosing Cholangitis (PSC)1
2CompletedTreatmentProgressive Familial Intrahepatic Cholestasis (PFIC)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
SolutionOral9.5 mg/1mL
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US11260053No2011-05-262031-05-26US flag
US11229647No2020-02-122040-02-12US flag
US11376251No2012-10-262032-10-26US flag
US11497745No2020-02-122040-02-12US flag

Properties

State
Liquid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility2.39e-05 mg/mLALOGPS
logP3.96ALOGPS
logP2.7Chemaxon
logS-7.5ALOGPS
pKa (Strongest Acidic)14.15Chemaxon
pKa (Strongest Basic)5.68Chemaxon
Physiological Charge1Chemaxon
Hydrogen Acceptor Count6Chemaxon
Hydrogen Donor Count1Chemaxon
Polar Surface Area70.08 Å2Chemaxon
Rotatable Bond Count13Chemaxon
Refractivity209.09 m3·mol-1Chemaxon
Polarizability78.83 Å3Chemaxon
Number of Rings6Chemaxon
Bioavailability0Chemaxon
Rule of FiveNoChemaxon
Ghose FilterNoChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleYesChemaxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Targets

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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]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
Curator comments
Maralixibat's inhibition of CYP3A4 is not expected to be clinically relevant.
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. FDA Approved Drug Products: Livmarli (Marilixibat) Oral Solution [Link]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates the Na(+)-independent transport of organic anions such as taurocholate, the prostaglandins PGD2, PGE1, PGE2, leukotriene C4, thromboxane B2 and iloprost.
Gene Name
SLCO2B1
Uniprot ID
O94956
Uniprot Name
Solute carrier organic anion transporter family member 2B1
Molecular Weight
76709.98 Da
References
  1. FDA Approved Drug Products: Livmarli (Marilixibat) Oral Solution [Link]

Drug created at December 15, 2020 18:16 / Updated at December 23, 2022 00:49