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| 25mg |
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Eliglustat tartrate (GENZ-112638; Genz-99067; Cerdelga), the tartrate salt of eliglustat, is a specific and orally bioactive glucocerebroside synthase inhibitor (IC50 = 24 nM) that has been approved by the FDA in August 2014 for the treatment for Gaucher's disease type 1 (GD1). It is commonly used as the tartrate salt, the compound is believed to work by inhibition of glucosylceramide synthase. According to an article in Journal of the American Medical Association the oral substrate reduction therapy resulted in 'significant improvements in spleen volume, hemoglobin level, liver volume, and platelet count' in untreated adults with Gaucher disease Type 1.
| ln Vitro |
Eliglustat tartrate is selective for the target enzyme and has good efficacy, with an IC50 of 24 nM [1]. Dose-dependent results were obtained by incubating K562 or B16/F10 cells with escalating concentrations of Genz-112638 (0.6-1000 nM) for 72 hours. GM1 and GM3 levels on the cell surface decreased. In K562 cells, the average IC50 value for GM1 cell surface presentation inhibition was 24 nM (range 14-34 nM), while in B16/F10 cells, the average IC50 value for GM3 inhibition was 29 nM (range 12-48 nM) [1].
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| ln Vivo |
In comparison to age-matched control animals, mice administered the medication prior to considerable substrate accumulation (10 weeks of age) displayed lower levels of glucosylceramide and fewer Gaucher cells in the liver, lungs, and spleen [1].
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| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion
A dose of agalsidase alfa in non end stage renal disease patients reaches a Cmax of 3710 ± 855 U/mL with an AUC of 256,958 ± 63,499 min\*U/mL. After nonspecific proteolysis, the amino acids from protein drugs are reused for protein synthesis or further broken down and eliminated by the kidneys. The volume of distribution at steady state in non end stage renal disease patients was approximately 17% of body weight regardless of sex. The clearance for doses of 0.007-0.2 mg/kg were 2.66 mL/min/kg for males and 2.10 mL/min/kg for females. Metabolism / Metabolites Data regarding the metabolism of agalsidase alfa is not readily available. However, protein drugs are expected to be degraded by proteases and other catalytic enzymes to smaller peptides and amino acids. Biological Half-Life The elimination half life was 108 ± 17 minutes for males and 89 ± 28 minutes for females. |
| Toxicity/Toxicokinetics |
Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation Because there is no published experience with eliglustat during breastfeeding, an alternate drug may be preferred, especially while nursing a newborn or preterm infant. ◉ 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 Agalsidase alfa is not expected to be protein bound in circulation. |
| References | |
| Additional Infomation |
Eliglustat tartrate is a tartrate that is the hemitartrate salt of eliglustat. A ceramide glucosyltransferase inhibitor used (as its tartrate salt) for treatment of Gaucher's disease. It has a role as an EC 2.4.1.80 (ceramide glucosyltransferase) inhibitor. It contains an eliglustat(1+).
Agalsidase alfa is a recombinant human α-galactosidase A similar to [agalsidase beta]. While patients generally do not experience a clinically significant difference in outcomes between the two drugs, some patients may experience greater benefit with agalsidase beta. Use of agalsidase beta has decreased in Europe, in favor of agalsidase alfa, after a contamination event in 2009. Agalsidase alfa was granted EMA approval on 3 August 2001. See also: Eliglustat (has active moiety); Agalsidase Beta (annotation moved to). Drug Indication Agalsidase alfa is indicated in the treatment of Fabry disease. Replagal is indicated for long-term enzyme-replacement therapy in patients with a confirmed diagnosis of Fabry disease (α-galactosidase-A deficiency). Mechanism of Action α-galactosidase A is uptaken by cells via the mannose 6 phosphate receptor. Agalsidase alfa hydrolyzes globotriaosylceramide and other glycosphingolipids that would normally be hydrolyzed by endogenous α-galactosidase A. Preventing the accumulation of glycosphingolipids prevents or reduces the severity of manifestations of Fabry disease such as renal failure, cardiomyopathy, or cerebrovascular events. Pharmacodynamics Agalsidase alfa is a recombinant human α-galactosidase A used as enzyme replacement therapy in the treatment of Fabry disease. It has a long duration of action and a wide therapeutic index. Patients should be counselled regarding the risk of infusion related reactions and hypersensitivity. |
| Molecular Formula |
2[C23H36N2O4].C4H6O6
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|---|---|
| Molecular Weight |
959.173
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| Exact Mass |
958.551
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| CAS # |
928659-70-5
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| Related CAS # |
Eliglustat;491833-29-5;Eliglustat-d15 tartrate;1884556-84-6
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| PubChem CID |
52918379
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| Appearance |
White to off-white solid powder
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| LogP |
6.298
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| Hydrogen Bond Donor Count |
8
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| Hydrogen Bond Acceptor Count |
16
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| Rotatable Bond Count |
25
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| Heavy Atom Count |
68
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| Complexity |
617
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| Defined Atom Stereocenter Count |
6
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| SMILES |
CCCCCCCC(=O)N[C@H](CN1CCCC1)[C@@H](C2=CC3=C(C=C2)OCCO3)O.CCCCCCCC(=O)N[C@H](CN1CCCC1)[C@@H](C2=CC3=C(C=C2)OCCO3)O.[C@@H]([C@H](C(=O)O)O)(C(=O)O)O
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| InChi Key |
KUBARPMUNHKBIQ-VTHUDJRQSA-N
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| InChi Code |
InChI=1S/2C23H36N2O4.C4H6O6/c2*1-2-3-4-5-6-9-22(26)24-19(17-25-12-7-8-13-25)23(27)18-10-11-20-21(16-18)29-15-14-28-20;5-1(3(7)8)2(6)4(9)10/h2*10-11,16,19,23,27H,2-9,12-15,17H2,1H3,(H,24,26);1-2,5-6H,(H,7,8)(H,9,10)/t2*19-,23-;1-,2-/m111/s1
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| Chemical Name |
N-[(1R,2R)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-hydroxy-3-pyrrolidin-1-ylpropan-2-yl]octanamide;(2R,3R)-2,3-dihydroxybutanedioic acid
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~100 mg/mL (~104.26 mM)
H2O : ≥ 50 mg/mL (~52.13 mM) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.75 mg/mL (2.87 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 27.5 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.75 mg/mL (2.87 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 27.5 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.75 mg/mL (2.87 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 150 mg/mL (156.39 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.0426 mL | 5.2128 mL | 10.4257 mL | |
| 5 mM | 0.2085 mL | 1.0426 mL | 2.0851 mL | |
| 10 mM | 0.1043 mL | 0.5213 mL | 1.0426 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.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT06143904 | COMPLETED | Drug: Genz-112638 Drug: Genz-112638 Drug: [14C]-Genz-112638 |
Gaucher's Disease Type I | Sanofi | 2009-06-03 | Phase 1 |
| NCT01074944 | COMPLETEDWITH RESULTS | Drug: Eliglustat tartrate | Gaucher Disease | Genzyme, a Sanofi Company | 2010-06 | Phase 3 |
| NCT02536911 | COMPLETED | Drug: eliglustat | Gaucher Disease | Genzyme, a Sanofi Company | 2015-09 | Phase 1 |
| NCT02536937 | COMPLETED | Drug: eliglustat | Gaucher Disease | Sanofi | 2015-09 | Phase 1 |
| NCT00891202 | COMPLETEDWITH RESULTS | Drug: Eliglustat tartrate Drug: Placebo |
Gaucher Disease, Type 1 | Genzyme, a Sanofi Company | 2009-11 | Phase 3 |
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