Identification
- Summary
Miglustat is a glucosylceramide synthase inhibitor used for the management of mild to moderate type I Gaucher disease for patients who are not candidates for whole enzyme replacement.
- Brand Names
- Opfolda, Zavesca
- Generic Name
- Miglustat
- DrugBank Accession Number
- DB00419
- Background
Miglustat, commonly marketed under the trade name Zavesca, is a drug used to treat Gaucher disease. It inhibits the enzyme glucosylceramide synthase, an essential enzyme for the synthesis of most glycosphingolipids. It is only used for patients who cannot be treated with enzyme replacement therapy with imiglucerase. Miglustat is now the first and only approved therapy for patients with Niemann-Pick disease type C (NP-C). It has recently been approved for treatment of progressive neurological symptoms in adult and pediatric patients in the European Union, Brazil, and South Korea. Miglustat was first developed as an anti-HIV agent in the 1990s. However, clinical experience with miglustat showed that therapeutic levels of the drug could not be achieved in patients without a high incidence of adverse effect.
- Type
- Small Molecule
- Groups
- Approved
- Structure
Structure for Miglustat (DB00419)
- Weight
- Average: 219.278
Monoisotopic: 219.147058165 - Chemical Formula
- C10H21NO4
- Synonyms
- 1,5-(butylimino)-1,5-dideoxy, D-glucitol
- AT2221
- BuDNJ
- Butyldeoxynojirimycin
- Miglustat
- Miglustatum
- N-(n-Butyl)deoxynojirimycin
- n-Butyl deoxynojirimycin
- N-butyl-1-deoxynojirimycin
- N-butyl-deoxynojirimycin
- N-Butylmoranoline
- NB-DNJ
- External IDs
- OGT 918
- OGT-918
- SC 48334
- SC-48334
- SC48334
Pharmacology
- Indication
For the treatment of adult patients with mild to moderate type 1 (nonneuropathic) Gaucher's disease for whom enzyme replacement therapy is not a therapeutic option (e.g. due to constraints such as allergy, hypersensitivity, or poor venous access). Now approved in some countries for the treatment of progressive neurological symptoms in adult and pediatric patients with Niemann-Pick disease type C (NP-C).
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Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Treatment of Mild, moderate gaucher disease, type 1 •••••••••••• ••••• ••• • ••••••••• ••• •••••• ••••••••••• ••••••• ••••••• - Contraindications & Blackbox Warnings
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Miglustat, an N-alkylated imino sugar, is a synthetic analogue of D-glucose. Miglustat is an inhibitor of the enzyme glucosylceramide synthase, which is a glucosyl transferase enzyme responsible for catalyzing the formation of glucosylceramide (glucocerebroside). Glucosylceramide is a substrate for the endogenous glucocerebrosidase, an enzyme that is deficient in Gaucher's disease. The accumulation of glucosylceramide due to the absence of glucocerebrosidase results in the storage of this material in the lysosomes of tissue macrophages, leading to widespread pathology due to infiltration of lipid-engorged macrophages in the viscera, lymph nodes, and bone marrow. This results in secondary hematologic consequences including sever anemia and thrombocytopenia, in addition to the characteristic progressive hepatosplenomegaly, as well as skeletal complications including osteonecrosis and osteopenia with secondary pathological fractures.
- Mechanism of action
Miglustat functions as a competitive and reversible inhibitor of the enzyme glucosylceramide synthase, the initial enzyme in a series of reactions which results in the synthesis of most glycosphingolipids. The goal of treatment with miglustat is to reduce the rate of glycosphingolipid biosynthesis so that the amount of glycosphingolipid substrate is reduced to a level which allows the residual activity of the deficient glucocerebrosidase enzyme to be more effective (substrate reduction therapy), reducing the accumulation of glucocerebroside in macrophages. In vitro and in vivo studies have shown that miglustat can reduce the synthesis of glucosylceramide-based glycosphingolipids. In clinical trials, miglustat improved liver and spleen volume, as well as hemoglobin concentration and platelet count. Inhibition of glycosphingolipid synthesis has also shown to reduce intracellular lipid storage, improve fluid-phase endosomal uptake and normalize lipid transport in peripheral blood B lymphocytes of NP-C patients, which results in a decrease in the potentially neurotoxic accumulation of gnagliosides GM2 and GM3, lactosylceramide and glucosylceramide, possibly preventing further neuronal damage. Other studies have also suggested that miglustat may indirectly modulate intracellular calcium homeostasis through its effects on glucosylceramide levels, and evidence has shown that an initiating factor in the pathogenesis of NP-C may be impaired calcium homeostasis related to sphingosine storage. Therefore, the effect that miglustat exerts on intracellular calcium levels may influence an important underlying pathogenic mechanism of NP-C.
Target Actions Organism ACeramide glucosyltransferase inhibitorHumans - Absorption
Mean oral bioavailability is 97%.
- Volume of distribution
Not Available
- Protein binding
Miglustat does not bind to plasma proteins.
- Metabolism
There is no evidence that miglustat is metabolized in humans.
- Route of elimination
Not Available
- Half-life
The effective half-life of miglustat is approximately 6 to 7 hours.
- Clearance
Not Available
- Adverse Effects
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Miglustat has been administered at doses of up to 3000 mg/day (approximately 10 times the recommended starting dose administered to Gaucher patients) for up to six months in Human Immunodeficiency Virus (HIV)-positive patients. Adverse events observed in the HIV studies included granulocytopenia, dizziness, and paresthesia. Leukopenia and neutropenia have also been observed in a similar group of patients receiving 800 mg/day or above.
- 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.No interactions found.
- Food Interactions
- Take at the same time every day.
- Take with or without food.
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 Miglustat hydrochloride Not Available 210110-90-0 QPAFAUYWVZMWPR-ZSOUGHPYSA-N - International/Other Brands
- Zavesca (Actelion Pharmaceuticals)
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Miglustat Dipharma Capsule 100 mg Oral Dipharma Arzneimittel Gmb H 2021-02-10 Not applicable EU 
Miglustat Dipharma Capsule 100 mg Oral Dipharma Arzneimittel Gmb H 2023-07-26 Not applicable EU Miglustat Dipharma Capsule 100 mg Oral Dipharma Arzneimittel Gmb H 2021-02-10 Not applicable EU Miglustat Gen.orph Capsule 100 mg Oral Gen.Orph 2020-12-16 Not applicable EU Miglustat Gen.orph Capsule 100 mg Oral Gen.Orph 2022-05-04 Not applicable EU - Generic Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Miglustat Capsule 100 mg/1 Oral Breckenridge Pharmaceutical, Inc. 2022-03-01 Not applicable US 
Miglustat Capsule 100 mg/1 Oral CoTherix, Inc. 2018-04-25 Not applicable US Miglustat Capsule 100 mg/1 Oral ANI Pharmaceuticals, Inc. 2018-04-17 Not applicable US Miglustat Capsule 100 mg/1 Oral Edenbridge Pharmaceuticals LLC. 2020-08-06 2023-10-31 US Sandoz Miglustat Capsule 100 mg Oral Sandoz Canada Incorporated 2020-04-20 Not applicable Canada 
Categories
- ATC Codes
- A16AX06 — Miglustat
- Drug Categories
- Alimentary Tract and Metabolism
- Alkaloids
- Anti-HIV Agents
- Anti-Infective Agents
- Carbohydrates
- Enzyme Inhibitors
- Gaucher Disease
- Glucosylceramide Synthase Inhibitor
- Glucosylceramide Synthase Inhibitors
- Glycoside Hydrolase Inhibitors
- Imines
- Imino Pyranoses
- Imino Sugars
- Other Miscellaneous Therapeutic Agents
- Piperidines
- Various Alimentary Tract and Metabolism Products
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as piperidines. These are compounds containing a piperidine ring, which is a saturated aliphatic six-member ring with one nitrogen atom and five carbon atoms.
- Kingdom
- Organic compounds
- Super Class
- Organoheterocyclic compounds
- Class
- Piperidines
- Sub Class
- Not Available
- Direct Parent
- Piperidines
- Alternative Parents
- Trialkylamines / Secondary alcohols / 1,2-aminoalcohols / Polyols / Azacyclic compounds / Primary alcohols / Organopnictogen compounds / Hydrocarbon derivatives
- Substituents
- 1,2-aminoalcohol / Alcohol / Aliphatic heteromonocyclic compound / Amine / Azacycle / Hydrocarbon derivative / Organic nitrogen compound / Organic oxygen compound / Organonitrogen compound / Organooxygen compound
- Molecular Framework
- Aliphatic heteromonocyclic compounds
- External Descriptors
- piperidines, tertiary amino compound (CHEBI:50381)
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- ADN3S497AZ
- CAS number
- 72599-27-0
- InChI Key
- UQRORFVVSGFNRO-UTINFBMNSA-N
- InChI
- InChI=1S/C10H21NO4/c1-2-3-4-11-5-8(13)10(15)9(14)7(11)6-12/h7-10,12-15H,2-6H2,1H3/t7-,8+,9-,10-/m1/s1
- IUPAC Name
- (2R,3R,4R,5S)-1-butyl-2-(hydroxymethyl)piperidine-3,4,5-triol
- SMILES
- CCCCN1C[C@H](O)[C@@H](O)[C@H](O)[C@H]1CO
References
- General References
- van Giersbergen PL, Dingemanse J: Influence of food intake on the pharmacokinetics of miglustat, an inhibitor of glucosylceramide synthase. J Clin Pharmacol. 2007 Oct;47(10):1277-82. Epub 2007 Aug 24. [Article]
- Weinreb NJ, Barranger JA, Charrow J, Grabowski GA, Mankin HJ, Mistry P: Guidance on the use of miglustat for treating patients with type 1 Gaucher disease. Am J Hematol. 2005 Nov;80(3):223-9. [Article]
- Patterson MC, Vecchio D, Prady H, Abel L, Wraith JE: Miglustat for treatment of Niemann-Pick C disease: a randomised controlled study. Lancet Neurol. 2007 Sep;6(9):765-72. [Article]
- Moyses C: Substrate reduction therapy: clinical evaluation in type 1 Gaucher disease. Philos Trans R Soc Lond B Biol Sci. 2003 May 29;358(1433):955-60. [Article]
- Wraith JE, Imrie J: New therapies in the management of Niemann-Pick type C disease: clinical utility of miglustat. Ther Clin Risk Manag. 2009;5:877-87. Epub 2009 Nov 18. [Article]
- McCormack PL, Goa KL: Miglustat. Drugs. 2003;63(22):2427-34; discussion 2435-6. [Article]
- Andersson U, Reinkensmeier G, Butters TD, Dwek RA, Platt FM: Inhibition of glycogen breakdown by imino sugars in vitro and in vivo. Biochem Pharmacol. 2004 Feb 15;67(4):697-705. [Article]
- FDA Approved Drug Products: ZAVESCA (miglustat) capsules [Link]
- External Links
- Human Metabolome Database
- HMDB0014563
- KEGG Drug
- D05032
- PubChem Compound
- 51634
- PubChem Substance
- 46506350
- ChemSpider
- 46764
- BindingDB
- 18355
- 402316
- ChEBI
- 50381
- ChEMBL
- CHEMBL1029
- ZINC
- ZINC000003794711
- Therapeutic Targets Database
- DAP000609
- PharmGKB
- PA10140
- PDBe Ligand
- NBV
- RxList
- RxList Drug Page
- Drugs.com
- Drugs.com Drug Page
- Wikipedia
- Miglustat
- PDB Entries
- 2v3d / 5ief
- FDA label
- Download (911 KB)
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 4 Completed Treatment Contraception 1 4 Completed Treatment Niemann-Pick Disease, Type C 1 4 Terminated Treatment GM1 Gangliosidoses / GM2 Gangliosidosis / Sandhoffs Disease / Tay-Sachs Disease 1 3 Active Not Recruiting Treatment Late-onset Pompe Disease 1 3 Completed Treatment Gaucher Disease, Type 1 1
Pharmacoeconomics
- Manufacturers
- Actelion pharmaceuticals ltd
- Packagers
- Actelion Pharmaceuticals Inc.
- Pharmaceutical Development and Manufacturing Services Ltd.
- Dosage Forms
Form Route Strength Capsule Oral 100 mg/1 Powder 1 kg/1kg Capsule Oral Capsule Oral 65 mg Capsule Oral 65 mg/1 Capsule Oral 100 mg Capsule, coated Oral 100 mg - Prices
Unit description Cost Unit Zavesca 100 mg capsule 160.67USD capsule DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US5525616 No 1996-06-11 2013-06-11 US US5472969 No 1995-12-05 2013-05-13 US US11753632 No 2015-09-30 2035-09-30 US US11278601 No 2016-12-29 2036-12-29 US US11278599 No 2013-03-07 2033-03-07 US US10961522 No 2021-03-30 2035-09-30 US US10857212 No 2020-12-08 2037-08-12 US US10512677 No 2019-12-24 2033-03-07 US US10208299 No 2019-02-19 2035-09-30 US
Properties
- State
- Solid
- Experimental Properties
Property Value Source melting point (°C) 169-172 °C Not Available water solubility Highly soluble in water (>1000 mg/mL as a free base). Not Available logP -0.6 Not Available - Predicted Properties
Property Value Source Water Solubility 331.0 mg/mL ALOGPS logP -1.1 ALOGPS logP -1.2 Chemaxon logS 0.18 ALOGPS pKa (Strongest Acidic) 12.9 Chemaxon pKa (Strongest Basic) 8.49 Chemaxon Physiological Charge 1 Chemaxon Hydrogen Acceptor Count 5 Chemaxon Hydrogen Donor Count 4 Chemaxon Polar Surface Area 84.16 Å2 Chemaxon Rotatable Bond Count 4 Chemaxon Refractivity 55.74 m3·mol-1 Chemaxon Polarizability 23.95 Å3 Chemaxon Number of Rings 1 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter No Chemaxon Veber's Rule No Chemaxon MDDR-like Rule No Chemaxon - Predicted ADMET Features
Property Value Probability Human Intestinal Absorption + 0.9092 Blood Brain Barrier - 0.9011 Caco-2 permeable - 0.6433 P-glycoprotein substrate Substrate 0.8088 P-glycoprotein inhibitor I Non-inhibitor 0.667 P-glycoprotein inhibitor II Non-inhibitor 0.9556 Renal organic cation transporter Non-inhibitor 0.757 CYP450 2C9 substrate Non-substrate 0.8224 CYP450 2D6 substrate Non-substrate 0.765 CYP450 3A4 substrate Non-substrate 0.5817 CYP450 1A2 substrate Non-inhibitor 0.9188 CYP450 2C9 inhibitor Non-inhibitor 0.8855 CYP450 2D6 inhibitor Non-inhibitor 0.9226 CYP450 2C19 inhibitor Non-inhibitor 0.9484 CYP450 3A4 inhibitor Non-inhibitor 0.9855 CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.9941 Ames test Non AMES toxic 0.8426 Carcinogenicity Non-carcinogens 0.9595 Biodegradation Not ready biodegradable 0.5763 Rat acute toxicity 2.1203 LD50, mol/kg Not applicable hERG inhibition (predictor I) Weak inhibitor 0.6675 hERG inhibition (predictor II) Non-inhibitor 0.8508
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted GC-MS Spectrum - GC-MS Predicted GC-MS splash10-0zos-3910000000-487652a19fde10ffe683 Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS splash10-00di-0090000000-67d12d358455133ef139 Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS splash10-014i-0290000000-1d6fe2d816b7f9a0957f Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS splash10-0fk9-2970000000-817317f8d1c96e109b30 Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS splash10-014i-0690000000-7acbe1d54f954f471843 Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS splash10-059x-9200000000-b9e57aa074ce0504de0a Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS splash10-0ab9-7900000000-b694ad05a2103ca16c1c Predicted 1H NMR Spectrum 1D NMR Not Applicable Predicted 13C NMR Spectrum 1D NMR Not Applicable - Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 155.3246872 predictedDarkChem Lite v0.1.0 [M-H]- 155.2952872 predictedDarkChem Lite v0.1.0 [M-H]- 158.4531872 predictedDarkChem Lite v0.1.0 [M-H]- 153.38017 predictedDeepCCS 1.0 (2019) [M+H]+ 155.6385872 predictedDarkChem Lite v0.1.0 [M+H]+ 155.6275872 predictedDarkChem Lite v0.1.0 [M+H]+ 158.7189872 predictedDarkChem Lite v0.1.0 [M+H]+ 155.73817 predictedDeepCCS 1.0 (2019) [M+Na]+ 155.4510872 predictedDarkChem Lite v0.1.0 [M+Na]+ 155.2228872 predictedDarkChem Lite v0.1.0 [M+Na]+ 158.3647872 predictedDarkChem Lite v0.1.0 [M+Na]+ 161.84079 predictedDeepCCS 1.0 (2019)
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Ceramide glucosyltransferase activity
- Specific Function
- Catalyzes the first glycosylation step in glycosphingolipid biosynthesis, the transfer of glucose to ceramide. May also serve as a "flippase".
- Gene Name
- UGCG
- Uniprot ID
- Q16739
- Uniprot Name
- Ceramide glucosyltransferase
- Molecular Weight
- 44853.255 Da
References
- Moyses C: Substrate reduction therapy: clinical evaluation in type 1 Gaucher disease. Philos Trans R Soc Lond B Biol Sci. 2003 May 29;358(1433):955-60. [Article]
- Weinreb NJ, Barranger JA, Charrow J, Grabowski GA, Mankin HJ, Mistry P: Guidance on the use of miglustat for treating patients with type 1 Gaucher disease. Am J Hematol. 2005 Nov;80(3):223-9. [Article]
- Chien YH, Lee NC, Tsai LK, Huang AC, Peng SF, Chen SJ, Hwu WL: Treatment of Niemann-Pick disease type C in two children with miglustat: initial responses and maintenance of effects over 1 year. J Inherit Metab Dis. 2007 Oct;30(5):826. Epub 2007 Jun 21. [Article]
- Treiber A, Morand O, Clozel M: The pharmacokinetics and tissue distribution of the glucosylceramide synthase inhibitor miglustat in the rat. Xenobiotica. 2007 Mar;37(3):298-314. [Article]
- Ficicioglu C: Review of miglustat for clinical management in Gaucher disease type 1. Ther Clin Risk Manag. 2008 Apr;4(2):425-31. [Article]
- Wraith JE, Imrie J: New therapies in the management of Niemann-Pick type C disease: clinical utility of miglustat. Ther Clin Risk Manag. 2009;5:877-87. Epub 2009 Nov 18. [Article]
- Pastores GM: Miglustat: substrate reduction therapy for lysosomal storage disorders associated with primary central nervous system involvement. Recent Pat CNS Drug Discov. 2006 Jan;1(1):77-82. [Article]
- McCormack PL, Goa KL: Miglustat. Drugs. 2003;63(22):2427-34; discussion 2435-6. [Article]
- Giraldo P, Latre P, Alfonso P, Acedo A, Alonso D, Barez A, Corrales A, Franco R, Roldan V, Serrano S, Pocovi M: Short-term effect of miglustat in every day clinical use in treatment-naive or previously treated patients with type 1 Gaucher's disease. Haematologica. 2006 May;91(5):703-6. Epub 2006 Apr 19. [Article]
- Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
Drug created at June 13, 2005 13:24 / Updated at February 20, 2024 23:55