| 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
In healthy adults, after a single oral dose of 1 mg to 500 mg of maraliciba, plasma concentrations below the limit of quantitation (0.25 ng/mL) are unreliable when the dose is below 20 mg, making it impossible to reliably estimate pharmacokinetic parameters. Following a single fasting 30 mg dose, the median Tmax was 0.75, and the mean (standard deviation) Cmax and AUClast were 1.65 (1.10) ng/mL and 3.43 (2.13) ng·h/mL, respectively. Maraliciba is poorly absorbed, and plasma concentrations are often below the limit of quantitation (0.25 ng/mL) even with single or multiple doses of the recommended dose. Following single oral administration of 30, 45, and 100 mg of malariziba liquid formulation in an empty stomach, both AUClast and Cmax increased in a dose-dependent manner, with AUClast and Cmax increasing 4.6-fold and 2.4-fold, respectively, when the dose increased from 30 mg to 100 mg. No drug accumulation was observed after single daily oral administration of up to 100 mg of malariziba in healthy adults. Consumption of a high-fat diet with a single oral dose of malariziba reduced its absorption rate and extent. The AUC and Cmax values of malariziba in a fed state were 64.8% to 85.8% lower than those after a 30 mg oral dose in an empty stomach. The effect of food on systemic exposure to malariziba was clinically insignificant. Fecal excretion is the primary route of elimination. Following a single oral dose of 5 mg of [14C]maralixibat, 73% of the dose was excreted in feces and 0.066% in urine. 94% of fecal excrement contained unchanged maralixibat. Metabolites/Metabolites: No maralixibat metabolites were detected in plasma. Three minor metabolites were identified after oral administration of [14C]maralixibat, accounting for <3% of the total fecal radioactivity associated with maralixibat. The structures of these metabolites have not been reported in the literature. Biological Half-Life: The mean half-life of maralixibat is 1.6 hours. |
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| Toxicity/Toxicokinetics |
Hepatotoxicity
In clinical trials of Maralixibat in children with Aragile syndrome, 24% of patients had serum ALT levels exceeding three times the upper limit of normal, and 2% had levels exceeding five times the upper limit of normal. Elevated ALT levels led to dose adjustments, treatment interruptions, or early discontinuation in up to 10% of patients. Serum transaminases in children with Aragile syndrome and other cholestatic liver diseases are typically elevated to 2 to 5 times the upper limit of normal, making it difficult to distinguish between spontaneous fluctuations in enzyme levels caused by the primary disease and the effects of Maralixibat treatment. In most cases, treatment can continue even with elevated serum enzyme levels, at least with a reduced dose. There are currently no reports of clinically significant liver injury with jaundice due to Maralixibat treatment, but the clinical use of this drug is limited. Probability Score: E (Suspected but not confirmed cause of clinically significant liver injury). Use during pregnancy and lactation ◉ Overview of use during lactation There is currently no information regarding the use of malariziba during lactation. Because malariziba is poorly absorbed orally and 90% is bound to plasma proteins, its concentration in breast milk may be very low. If a mother needs to take malariziba, this is not a reason to discontinue breastfeeding. ◉ Effects on breastfed infants As of the revision date, no relevant published information was found. ◉ Effects on lactation and breast milk As of the revision date, no relevant published information was found. Protein binding Malariziba binds to plasma proteins 91% in vitro. |
| Additional Infomation |
Pharmacodynamics
Maralixibat is indicated for the treatment of cholestatic pruritus in patients at least 1 year old with Aragile syndrome. Because it requires only once-daily administration, its duration of action is moderate; and its therapeutic index is broad, allowing patients to safely tolerate single doses up to 18 times the normal dose. Patients should be informed of the risks of abnormal liver function, 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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