Identification

Name
Miglustat
Accession Number
DB00419  (APRD01118)
Type
Small Molecule
Groups
Approved
Description

Miglustat 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 marketed under the trade name Zavesca. 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.

Structure
Thumb
Synonyms
  • BuDNJ
  • Butyldeoxynojirimycin
  • Miglustatum
  • N-(N-Butyl)deoxynojirimycin
  • N-Butyl deoxynojirimycin
  • N-Butyl-1-deoxynojirimycin
  • N-Butylmoranoline
  • NB-dnj
  • SC-48334
External IDs
OGT 918 / OGT-918
Product Ingredients
IngredientUNIICASInChI Key
Miglustat HydrochlorideNot AvailableNot AvailableUQRORFVVSGFNRO-UTINFBMNSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
MiglustatCapsule100 mg/1OralCo Therix, Inc.2016-12-09Not applicableUs
Sandoz MiglustatCapsule100 mgOralSandoz Canada IncorporatedNot applicableNot applicableCanada
ZavescaCapsule100 mgOralActelion2004-05-26Not applicableCanada
ZavescaCapsule100 mgOralActelion2002-11-20Not applicableEu
ZavescaCapsule100 mg/1OralActelion2003-07-31Not applicableUs
International/Other Brands
Zavesca
Categories
UNII
ADN3S497AZ
CAS number
72599-27-0
Weight
Average: 219.278
Monoisotopic: 219.147058165
Chemical Formula
C10H21NO4
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

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).

Structured Indications
Pharmacodynamics

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.

TargetActionsOrganism
ACeramide glucosyltransferase
inhibitor
Human
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
Toxicity

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.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteractionDrug group
BendroflumethiazideThe therapeutic efficacy of Miglustat can be decreased when used in combination with Bendroflumethiazide.Approved
ChlorothiazideThe therapeutic efficacy of Miglustat can be decreased when used in combination with Chlorothiazide.Approved, Vet Approved
ChlorthalidoneThe therapeutic efficacy of Miglustat can be decreased when used in combination with Chlorthalidone.Approved
CyclopenthiazideThe therapeutic efficacy of Miglustat can be decreased when used in combination with Cyclopenthiazide.Experimental
HydrochlorothiazideThe therapeutic efficacy of Miglustat can be decreased when used in combination with Hydrochlorothiazide.Approved, Vet Approved
HydroflumethiazideThe therapeutic efficacy of Miglustat can be decreased when used in combination with Hydroflumethiazide.Approved, Investigational
IndapamideThe therapeutic efficacy of Miglustat can be decreased when used in combination with Indapamide.Approved
Lipoic AcidLipoic Acid may increase the hypoglycemic activities of Miglustat.Approved, Nutraceutical
MedrogestoneThe serum concentration of Miglustat can be decreased when it is combined with Medrogestone.Approved
MethyclothiazideThe therapeutic efficacy of Miglustat can be decreased when used in combination with Methyclothiazide.Approved
MetolazoneThe therapeutic efficacy of Miglustat can be decreased when used in combination with Metolazone.Approved
PolythiazideThe therapeutic efficacy of Miglustat can be decreased when used in combination with Polythiazide.Approved
PregabalinThe risk or severity of heart failure can be increased when Pregabalin is combined with Miglustat.Approved, Illicit, Investigational
QuinethazoneThe therapeutic efficacy of Miglustat can be decreased when used in combination with Quinethazone.Approved
TrichlormethiazideThe therapeutic efficacy of Miglustat can be decreased when used in combination with Trichlormethiazide.Approved, Vet Approved
UbidecarenoneThe therapeutic efficacy of Miglustat can be increased when used in combination with Ubidecarenone.Approved, Investigational, Nutraceutical
Food Interactions
  • Take without regard to meals, but always at the same time and in the same way.

References

General References
  1. 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. [PubMed:17720777]
  2. 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. [PubMed:16247743]
  3. 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. [PubMed:17689147]
  4. 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. [PubMed:12803929]
  5. 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. [PubMed:19956552]
  6. McCormack PL, Goa KL: Miglustat. Drugs. 2003;63(22):2427-34; discussion 2435-6. [PubMed:14609352]
External Links
Human Metabolome Database
HMDB0014563
PubChem Compound
51634
PubChem Substance
46506350
ChemSpider
46764
BindingDB
18355
ChEBI
50381
ChEMBL
CHEMBL1029
Therapeutic Targets Database
DAP000609
PharmGKB
PA10140
HET
NBV
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Miglustat
ATC Codes
A16AX06 — Miglustat
AHFS Codes
  • 92:00.00 — Miscellaneous Therapeutic Agents
PDB Entries
2v3d / 5ief
FDA label
Download (911 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentHuman Immunodeficiency Virus (HIV) Infections1
1RecruitingTreatmentDrug hypersensitivity reaction / Pompe's Disease1
1, 2Active Not RecruitingTreatmentPompe's Disease1
2CompletedTreatmentCystic Fibrosis (CF)2
2CompletedTreatmentGangliosidoses GM21
2CompletedTreatmentGaucher's Disease1
2CompletedTreatmentHuman Immunodeficiency Virus (HIV) Infections2
2CompletedTreatmentNiemann-Pick Type C Disease1
2TerminatedTreatmentCystic Fibrosis (CF)1
2, 3RecruitingTreatmentCystic Fibrosis (CF)1
3CompletedTreatmentGangliosidoses, GM2 / Sandhoff Disease / Tay-Sachs1
3CompletedTreatmentGaucher's Disease Type 11
3CompletedTreatmentNiemann-Pick Disease Type C1
4CompletedTreatmentContraception1
4RecruitingTreatmentGangliosidoses, GM2 / GM1 Gangliosidoses / Sandhoff Disease / Tay-Sachs Disease1
Not AvailableCompletedNot AvailablePompe's Disease1
Not AvailableRecruitingTreatmentGaucher's Disease1

Pharmacoeconomics

Manufacturers
  • Actelion pharmaceuticals ltd
Packagers
Dosage forms
FormRouteStrength
CapsuleOral100 mg
CapsuleOral100 mg/1
Prices
Unit descriptionCostUnit
Zavesca 100 mg capsule160.67USD capsule
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US5525616No1993-06-112013-06-11Us
US5472969No1993-05-132013-05-13Us

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)169-172 °CNot Available
water solubilityHighly soluble in water (>1000 mg/mL as a free base).Not Available
logP-0.6Not Available
Predicted Properties
PropertyValueSource
Water Solubility331.0 mg/mLALOGPS
logP-1.1ALOGPS
logP-1.2ChemAxon
logS0.18ALOGPS
pKa (Strongest Acidic)12.9ChemAxon
pKa (Strongest Basic)8.49ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count4ChemAxon
Polar Surface Area84.16 Å2ChemAxon
Rotatable Bond Count4ChemAxon
Refractivity55.74 m3·mol-1ChemAxon
Polarizability23.99 Å3ChemAxon
Number of Rings1ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9092
Blood Brain Barrier-0.9011
Caco-2 permeable-0.6433
P-glycoprotein substrateSubstrate0.8088
P-glycoprotein inhibitor INon-inhibitor0.667
P-glycoprotein inhibitor IINon-inhibitor0.9556
Renal organic cation transporterNon-inhibitor0.757
CYP450 2C9 substrateNon-substrate0.8224
CYP450 2D6 substrateNon-substrate0.765
CYP450 3A4 substrateNon-substrate0.5817
CYP450 1A2 substrateNon-inhibitor0.9188
CYP450 2C9 inhibitorNon-inhibitor0.8855
CYP450 2D6 inhibitorNon-inhibitor0.9226
CYP450 2C19 inhibitorNon-inhibitor0.9484
CYP450 3A4 inhibitorNon-inhibitor0.9855
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9941
Ames testNon AMES toxic0.8426
CarcinogenicityNon-carcinogens0.9595
BiodegradationNot ready biodegradable0.5763
Rat acute toxicity2.1203 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.6675
hERG inhibition (predictor II)Non-inhibitor0.8508
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

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
Piperidine / 1,2-aminoalcohol / Secondary alcohol / Tertiary aliphatic amine / Tertiary amine / Polyol / Azacycle / Organic nitrogen compound / Hydrocarbon derivative / Primary alcohol
Molecular Framework
Aliphatic heteromonocyclic compounds
External Descriptors
piperidines, tertiary amino compound (CHEBI:50381)

Targets

Kind
Protein
Organism
Human
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
  1. 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. [PubMed:12803929]
  2. 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. [PubMed:16247743]
  3. 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. [PubMed:17603755]
  4. 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. [PubMed:17624027]
  5. Ficicioglu C: Review of miglustat for clinical management in Gaucher disease type 1. Ther Clin Risk Manag. 2008 Apr;4(2):425-31. [PubMed:18728838]
  6. 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. [PubMed:19956552]
  7. 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. [PubMed:18221193]
  8. McCormack PL, Goa KL: Miglustat. Drugs. 2003;63(22):2427-34; discussion 2435-6. [PubMed:14609352]
  9. 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. [PubMed:16627252]
  10. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]

Drug created on June 13, 2005 07:24 / Updated on January 22, 2018 10:46