| Size | Price | |
|---|---|---|
| 500mg | ||
| 1g | ||
| Other Sizes |
Maralixibat (formerly SHP-625; LUM-001; lopixibat; Livmarli) is an ileal bile acid transporter inhibitor approved for treatment of cholestatic pruritus associated with Alagille syndrome. It was approved for medical use in the United States in September 2021.
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion
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. 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. 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. No accumulation of maralixibat was observed following repeated oral administration of maralixibat in healthy adults at doses up to 100 mg once daily. 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. 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. Metabolism / Metabolites 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. The structures of these metabolites have not been defined in the literature. Biological Half-Life The mean half life of maralixibat is 1.6 hours. |
|---|---|
| Toxicity/Toxicokinetics |
Hepatotoxicity
In trials of maralixibat in children with Alagille syndrome, serum ALT levels rose to greater than 3 times ULN in 24% of patients and above 5 times ULN in 2%. The ALT elevations led to dose modification, interruption or therapy or early discontinuation in up to 10% of patients. Children with Alagille syndrome and other pediatric cholestatic liver diseases typically have serum aminotransferase elevations in the range of 2 to 5 times ULN, and it is can be difficult to distinguish between spontaneous fluctuations in enzyme levels due to the underlying disease vs effects of maralixibat therapy. In most instances, therapy can be continued despite the serum enzyme elevations, at least at a reduced dosage. There have been no reports of clinically apparent liver injury with jaundice attributed to maralixibat therapy, but it has had limited general clinical use. Likelihood score: E* (suspected but unproven cause of clinically apparent liver injury). Effects During Pregnancy and Lactation ◉ Summary of Use during Lactation No information is available on the use of maralixibat during breastfeeding. Because maralixibat is poorly absorbed orally and 90% bound to plasma proteins, the amount in milk is likely to be low. If maralixibat is required by the mother, it is not a reason to discontinue breastfeeding. ◉ Effects in Breastfed Infants Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk Relevant published information was not found as of the revision date. Protein Binding Maralixibat is 91% bound to plasma proteins _in vitro_. |
| Additional Infomation |
Pharmacodynamics
Maralixibat is indicated in the treatment of cholestatic pruritus in patients with Alagille syndrome who are at least 1 year old. 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. Patients should be counselled regarding the risks of liver test abnormalities, gastrointestinal adverse reactions, and fat-soluble vitamin deficiencies. |
| Molecular Formula |
C40H56N3O4S+
|
|---|---|
| Molecular Weight |
674.96
|
| Exact Mass |
674.398
|
| CAS # |
716313-53-0
|
| Related CAS # |
228113-66-4 (chloride) 716313-53-0 (cation)
|
| PubChem CID |
9831643
|
| Appearance |
Typically exists as solid at room temperature
|
| LogP |
4.13
|
| Hydrogen Bond Donor Count |
1
|
| Hydrogen Bond Acceptor Count |
6
|
| Rotatable Bond Count |
13
|
| Heavy Atom Count |
48
|
| Complexity |
1080
|
| Defined Atom Stereocenter Count |
2
|
| SMILES |
S1(C2C=CC(=CC=2[C@@H](C2C=CC(=CC=2)OCC2C=CC(=CC=2)C[N+]23CCN(CC2)CC3)[C@H](C(CCCC)(CCCC)C1)O)N(C)C)(=O)=O
|
| InChi Key |
ISZDVJLIDBLODR-RUKDTIIFSA-M
|
| InChi Code |
InChI=1S/C40H56N3O4S.BrH/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,5-8,19-26,28-30H2,1-4H31H/q+1/p-1/t38-,39-/m1./s1
|
| Chemical Name |
1-(4-((4-((4R,5R)-3,3-dibutyl-7-(dimethylamino)-4-hydroxy-1,1-dioxido-2,3,4,5-tetrahydrobenzo[b]thiepin-5-yl)phenoxy)methyl)benzyl)-1,4-diazabicyclo[2.2.2]octan-1-ium bromide
|
| Synonyms |
SHP625 SHP-625 LUM-001 LUM001lopixibatLivmarli Maralixibat bromide
|
| HS Tariff Code |
2934.99.9001
|
| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
|
| Solubility (In Vitro) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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|---|---|
| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.4816 mL | 7.4078 mL | 14.8157 mL | |
| 5 mM | 0.2963 mL | 1.4816 mL | 2.9631 mL | |
| 10 mM | 0.1482 mL | 0.7408 mL | 1.4816 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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