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
- 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 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
Reduce drug development failure ratesBuild, train, & validate machine-learning modelswith evidence-based and structured datasets.Build, train, & validate predictive machine-learning models with structured datasets.- 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 •••••••••••• •••••••• - Contraindications & Blackbox Warnings
- Prevent Adverse Drug Events TodayTap into our Clinical API for life-saving information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.Avoid life-threatening adverse drug events with our Clinical API
- 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 inhibitorHumans - 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 Tmax was 0.75 and mean (SD) Cmax and AUClast 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, AUClast and Cmax 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 Cmax 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
- Improve decision support & research outcomesWith structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates. View sample adverse effects data in our new Data Library!Improve decision support & research outcomes with our structured adverse effects data.
- 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 Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">
- Not Available
Interactions
- Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">
- 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.
Drug Interaction Integrate drug-drug
interactions in your softwareAsunaprevir 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.
Products
- Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.
- 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/1mL Oral Mirum Pharmaceuticals Inc. 2021-09-29 Not applicable US Livmarli Solution 9.5 mg/ml Oral Mirum Pharmaceuticals International B.V. 2023-02-08 Not applicable EU Livmarli Solution 9.5 mg / mL Oral Mirum Pharmaceuticals, Inc. 2023-08-11 Not applicable Canada
Categories
- ATC Codes
- A05AX04 — Maralixibat chloride
- 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
- 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]
- 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]
- FDA Approved Drug Products: Livmarli (Marilixibat) Oral Solution [Link]
- EMA Summary of Opinion: Livmarli (maralixibat chloride) [Link]
- EMA Approved Drug Products: Livmarli (maralixibat) Oral Solution [Link]
- 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]
- Health Canada Approved Drug Products: LIVMARLI (Maralixibat) Oral Solution [Link]
- FDA Approved Drug Products: LIVMARLI® (maralixibat) oral solution (September 2023) [Link]
- External Links
- ChemSpider
- 8007375
- BindingDB
- 50140282
- 2571074
- ChEMBL
- CHEMBL363392
- PharmGKB
- PA166268803
- Wikipedia
- Maralixibat_chloride
Clinical Trials
- Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">
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 US US11229647 No 2020-02-12 2040-02-12 US US11376251 No 2012-10-26 2032-10-26 US US11497745 No 2020-02-12 2040-02-12 US
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
![](https://go.drugbank.com/assets/locked/DrugTargets2-682eb846d210ae4bf33ca03febccfb57bb1c61318e699b729e5df4dfab2c5b67.png)
- 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
- 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]
- 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
- 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
- FDA Approved Drug Products: Livmarli (Marilixibat) Oral Solution [Link]
Drug created at December 15, 2020 18:16 / Updated at September 12, 2023 18:32