Eliglustat

Identification

Summary

Eliglustat is a glucosylceramide synthase used to treat type 1 Gaucher disease in patients who are CYP2D6 extensive, intermediate, or poor metabolizers, based on the FDA-approved test.

Brand Names
Cerdelga
Generic Name
Eliglustat
DrugBank Accession Number
DB09039
Background

Eliglustat, marketed by Genzyme as CERDELGA, is a glucosylceramide synthase inhibitor indicated for the long-term treatment of type 1 Gaucher disease. Patients selected for treatment with Eliglustat undergo an FDA approved genotype test to establish if they are CYP2D6 EM (extensive metabolizers), IM (intermediate metabolizers), or PM (poor metabolizers), as the results of this test dictate the dosage of Eliglustat recommended. There are no recommended dosing guidelines for CYP2D6 ultra-rapid or indeterminate metabolizers. Eliglustat was approved for use by the FDA in August 2014.

Type
Small Molecule
Groups
Approved
Structure
Thumb
Weight
Average: 404.551
Monoisotopic: 404.267507647
Chemical Formula
C23H36N2O4
Synonyms
  • Eliglustat
  • éliglustat
  • Eliglustatum
  • N-[(1R,2R)-1-(2,3-Dihydro-1,4-benzodioxin-6-yl)-1-hydroxy-3-(1-pyrrolidinyl)-2-propanyl]octanamide
External IDs
  • GENZ 99067
  • GENZ-99067

Pharmacology

Indication

Eliglustat is indicated for the long-term treatment of type 1 Gaucher disease in adult patients who are CYP2D6 extensive metabolizers (EMs), intermediate metabolizers (IMs), or poor metabolizers (PMs) as detected by an FDA-cleared test.Label

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

According to pharmacokinetic and pharmacodynamic modelling, plasma concentrations of 500ng/mL of eliglustat are predicted to increase mean concentration in the PR, QRS, and QTcF intervals of 22, 7, and 13 msec, respectively. (Taken from Cerdelga prescribing information).

Mechanism of action

Eliglustat is a glucosylceramide synthase (IC50 = 10 ng/mL) specific inhibitor that acts as a substrate inhibitor of glucosylceramide.

TargetActionsOrganism
ACeramide glucosyltransferase
antagonist
Humans
Absorption

In CYP2D6 EMs (extensive metabolizers), median time to reach maximum plasma concentrations (tmax) occurs at 1.5 to 2 hours following multiple doses of eliglustat 84 mg twice daily.

Volume of distribution

835 L in CYP2D6 EMs (extensive metabolizers).

Protein binding

76 to 83%.

Metabolism

Extensively metabolized, primarily by CYP2D6 and less so by CYP3A4. No active metabolites have been identified.

Route of elimination

Urine (41.8%) and feces (51.4%), mainly as metabolites after oral administration.

Half-life

6.5 hours in EM (extensive metabolizers) and 8.9 hours in PM (poor metabolizers).

Clearance

88 L/h (8.8%) in CYP2D6 EM (extensive metabolizers).

Adverse Effects
Adverseeffects
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Toxicity

In rats, eliglustat increased pre-implantation loss at 30 and 100 mg/kg/day. In male mature rats, eliglustat showed reversible adverse affects on sperm morphology, germ cell necrosis, and sloughed cells in the epididymis.

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Interacting Gene/EnzymeAllele nameGenotype(s)Defining Change(s)Type(s)DescriptionDetails
Cytochrome P450 2D6CYP2D6*3Not AvailableC alleleEffect InferredPoor drug metabolizer, lower dose requirement.Details
Cytochrome P450 2D6CYP2D6*4Not AvailableC alleleEffect InferredPoor drug metabolizer, lower dose requirement.Details
Cytochrome P450 2D6CYP2D6*5Not AvailableWhole-gene deletionEffect InferredPoor drug metabolizer, lower dose requirement.Details
Cytochrome P450 2D6CYP2D6*6Not Available1707delTEffect InferredPoor drug metabolizer, lower dose requirement.Details
Cytochrome P450 2D6CYP2D6*7Not Available2935A>CEffect InferredPoor drug metabolizer, lower dose requirement.Details
Cytochrome P450 2D6CYP2D6*8Not Available1758G>TEffect InferredPoor drug metabolizer, lower dose requirement.Details
Cytochrome P450 2D6CYP2D6*11Not Available883G>CEffect InferredPoor drug metabolizer, lower dose requirement.Details
Cytochrome P450 2D6CYP2D6*12Not Available124G>AEffect InferredPoor drug metabolizer, lower dose requirement.Details
Cytochrome P450 2D6CYP2D6*13Not AvailableCYP2D7/2D6 hybrid gene structureEffect InferredPoor drug metabolizer, lower dose requirement.Details
Cytochrome P450 2D6CYP2D6*14ANot Available1758G>AEffect InferredPoor drug metabolizer, lower dose requirement.Details
Cytochrome P450 2D6CYP2D6*15Not Available137insT, 137_138insTEffect InferredPoor drug metabolizer, lower dose requirement.Details
Cytochrome P450 2D6CYP2D6*19Not Available2539_2542delAACTEffect InferredPoor drug metabolizer, lower dose requirement.Details
Cytochrome P450 2D6CYP2D6*20Not Available1973_1974insGEffect InferredPoor drug metabolizer, lower dose requirement.Details
Cytochrome P450 2D6CYP2D6*21Not Available2573insCEffect InferredPoor drug metabolizer, lower dose requirement.Details
Cytochrome P450 2D6CYP2D6*31Not Available-1770G>A / -1584C>G  … show all Effect InferredPoor drug metabolizer, lower dose requirement.Details
Cytochrome P450 2D6CYP2D6*36Not Available100C>T / -1426C>T  … show all Effect InferredPoor drug metabolizer, lower dose requirement.Details
Cytochrome P450 2D6CYP2D6*38Not Available2587_2590delGACTEffect InferredPoor drug metabolizer, lower dose requirement.Details
Cytochrome P450 2D6CYP2D6*40Not Available1863_1864ins(TTT CGC CCC)2Effect InferredPoor drug metabolizer, lower dose requirement.Details
Cytochrome P450 2D6CYP2D6*42Not Available3259_3260insGTEffect InferredPoor drug metabolizer, lower dose requirement.Details
Cytochrome P450 2D6CYP2D6*44Not Available2950G>CEffect InferredPoor drug metabolizer, lower dose requirement.Details
Cytochrome P450 2D6CYP2D6*47Not Available100C>T / -1426C>T  … show all Effect InferredPoor drug metabolizer, lower dose requirement.Details
Cytochrome P450 2D6CYP2D6*51Not Available-1584C>G / -1235A>G  … show all Effect InferredPoor drug metabolizer, lower dose requirement.Details
Cytochrome P450 2D6CYP2D6*56Not Available3201C>TEffect InferredPoor drug metabolizer, lower dose requirement.Details
Cytochrome P450 2D6CYP2D6*57Not Available100C>T / 310G>T  … show all Effect InferredPoor drug metabolizer, lower dose requirement.Details
Cytochrome P450 2D6CYP2D6*62Not Available4044C>TEffect InferredPoor drug metabolizer, lower dose requirement.Details
Cytochrome P450 2D6CYP2D6*68ANot Available-1426C>T / -1235A>G  … show all Effect InferredPoor drug metabolizer, lower dose requirement.Details
Cytochrome P450 2D6CYP2D6*68BNot AvailableSimilar but not identical switch region compared to CYP2D6*68A. Found in tandem arrangement with CYP2D6*4.Effect InferredPoor drug metabolizer, lower dose requirement.Details
Cytochrome P450 2D6CYP2D6*69Not Available2988G>A / -1426C>T  … show all Effect InferredPoor drug metabolizer, lower dose requirement.Details
Cytochrome P450 2D6CYP2D6*92Not Available1995delCEffect InferredPoor drug metabolizer, lower dose requirement.Details
Cytochrome P450 2D6CYP2D6*100Not Available-1426C>T / -1235A>G  … show all Effect InferredPoor drug metabolizer, lower dose requirement.Details
Cytochrome P450 2D6CYP2D6*101Not Available-1426C>T / -1235A>G  … show all Effect InferredPoor drug metabolizer, lower dose requirement.Details
Cytochrome P450 2D6CYP2D6*1XNNot AvailableNormal allele duplicated.Effect InferredReduced efficacy.Details
Cytochrome P450 2D6CYP2D6*2XNNot Available2850C>T / 4180G>C  … show all Effect InferredReduced efficacy.Details

Interactions

Drug Interactions
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.
DrugInteraction
AbametapirThe serum concentration of Eliglustat can be increased when it is combined with Abametapir.
AbataceptThe metabolism of Eliglustat can be increased when combined with Abatacept.
AbemaciclibThe serum concentration of Abemaciclib can be increased when it is combined with Eliglustat.
AbirateroneThe metabolism of Eliglustat can be decreased when combined with Abiraterone.
AcalabrutinibThe metabolism of Eliglustat can be decreased when combined with Acalabrutinib.
AcebutololThe metabolism of Eliglustat can be decreased when combined with Acebutolol.
AcetaminophenThe metabolism of Eliglustat can be decreased when combined with Acetaminophen.
AcetazolamideThe metabolism of Eliglustat can be decreased when combined with Acetazolamide.
AcrivastineThe risk or severity of QTc prolongation can be increased when Acrivastine is combined with Eliglustat.
AdalimumabThe metabolism of Eliglustat can be increased when combined with Adalimumab.
Interactions
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Food Interactions
  • Avoid grapefruit products. Grapefruit inhibits the CYP3A4 metabolism of eliglustat, which may increase its serum concentration.
  • Avoid St. John's Wort. This herb induces the CYP3A metabolism of eliglustat and may reduce its serum concentration.
  • Take with or without food.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Eliglustat tartrateN0493335P3928659-70-5KUBARPMUNHKBIQ-VTHUDJRQSA-N
International/Other Brands
Cerdelga (Genzyme Corporation)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
CerdelgaCapsule84 mgOralGenzyme Europe Bv2016-09-08Not applicableEU flag
CerdelgaCapsule84 mgOralGenzyme Europe Bv2016-09-08Not applicableEU flag
CerdelgaCapsule84 mgOralSanofi Genzyme, a Division of Sanofi Aventis Canada Inc2017-07-26Not applicableCanada flag
CerdelgaCapsule84 mgOralGenzyme Europe Bv2016-09-08Not applicableEU flag
CerdelgaCapsule84 mg/1OralGenzyme Corporation2014-09-03Not applicableUS flag

Categories

ATC Codes
A16AX10 — Eliglustat
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as benzo-1,4-dioxanes. These are heterocyclic compounds containing a benzene ring fused to a 1,4-dioxane ring.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Benzodioxanes
Sub Class
Benzo-1,4-dioxanes
Direct Parent
Benzo-1,4-dioxanes
Alternative Parents
Alkyl aryl ethers / Aralkylamines / Para dioxins / N-alkylpyrrolidines / N-acyl amines / Benzenoids / 1,3-aminoalcohols / Trialkylamines / Secondary carboxylic acid amides / Secondary alcohols
show 8 more
Substituents
1,3-aminoalcohol / Alcohol / Alkyl aryl ether / Amine / Amino acid or derivatives / Aralkylamine / Aromatic alcohol / Aromatic heteropolycyclic compound / Azacycle / Benzenoid
show 23 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
secondary alcohol, carboxamide, N-alkylpyrrolidine, benzodioxine (CHEBI:82752)
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
DR40J4WA67
CAS number
491833-29-5
InChI Key
FJZZPCZKBUKGGU-AUSIDOKSSA-N
InChI
InChI=1S/C23H36N2O4/c1-2-3-4-5-6-9-22(26)24-19(17-25-12-7-8-13-25)23(27)18-10-11-20-21(16-18)29-15-14-28-20/h10-11,16,19,23,27H,2-9,12-15,17H2,1H3,(H,24,26)/t19-,23-/m1/s1
IUPAC Name
N-[(1R,2R)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl]octanamide
SMILES
CCCCCCCC(=O)N[C@H](CN1CCCC1)[C@H](O)C1=CC=C2OCCOC2=C1

References

General References
  1. Poole RM: Eliglustat: first global approval. Drugs. 2014 Oct;74(15):1829-36. doi: 10.1007/s40265-014-0296-3. [Article]
  2. McEachern KA, Fung J, Komarnitsky S, Siegel CS, Chuang WL, Hutto E, Shayman JA, Grabowski GA, Aerts JM, Cheng SH, Copeland DP, Marshall J: A specific and potent inhibitor of glucosylceramide synthase for substrate inhibition therapy of Gaucher disease. Mol Genet Metab. 2007 Jul;91(3):259-67. Epub 2007 May 16. [Article]
KEGG Drug
D09893
PubChem Compound
23652731
PubChem Substance
310264987
ChemSpider
28475348
RxNav
1547220
ChEBI
82752
ChEMBL
CHEMBL2110588
ZINC
ZINC000072267023
PharmGKB
PA166123486
Wikipedia
Eliglustat
FDA label
Download (376 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3CompletedTreatmentGaucher Disease, Type 12
3CompletedTreatmentGaucher's Disease2
3RecruitingTreatmentGaucher Disease, Type 1 / Gaucher Disease, Type III1
2CompletedTreatmentCerebroside Lipidosis Syndrome / Gaucher Disease, Non-Neuronopathic Form / Gaucher Disease, Type 1 / Glucocerebrosidase Deficiency Disease / Glucosylceramide Beta-Glucosidase Deficiency Disease1
1CompletedNot AvailableHealthy Subjects (HS)1
1CompletedBasic ScienceHealthy Subjects (HS)1
1CompletedTreatmentGaucher's Disease3
1CompletedTreatmentHealthy Subjects (HS)1
1RecruitingTreatmentMalignancies, Hematologic / Tumors, Solid1
Not AvailableActive Not RecruitingTreatmentGaucher Disease, Type III1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
CapsuleOral84 mg/1
CapsuleOral
Capsule, coatedOral84 mg
CapsuleOral84 mg
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US6916802No2005-07-122022-04-29US flag
US7615573No2009-11-102022-04-29US flag
US7196205No2007-03-272022-04-29US flag
US7253185No2007-08-072022-04-29US flag
US10888547No2021-01-122031-01-31US flag
US10888544No2021-01-122038-12-13US flag

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.113 mg/mLALOGPS
logP3.44ALOGPS
logP3.21ChemAxon
logS-3.6ALOGPS
pKa (Strongest Acidic)13.51ChemAxon
pKa (Strongest Basic)8.17ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area71.03 Å2ChemAxon
Rotatable Bond Count11ChemAxon
Refractivity113.76 m3·mol-1ChemAxon
Polarizability46.82 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
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

Targets

Drugtargets2
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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
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. Poole RM: Eliglustat: first global approval. Drugs. 2014 Oct;74(15):1829-36. doi: 10.1007/s40265-014-0296-3. [Article]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic...
Gene Name
CYP2D6
Uniprot ID
P10635
Uniprot Name
Cytochrome P450 2D6
Molecular Weight
55768.94 Da
References
  1. Poole RM: Eliglustat: first global approval. Drugs. 2014 Oct;74(15):1829-36. doi: 10.1007/s40265-014-0296-3. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Poole RM: Eliglustat: first global approval. Drugs. 2014 Oct;74(15):1829-36. doi: 10.1007/s40265-014-0296-3. [Article]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da

Drug created on April 02, 2015 16:54 / Updated on October 24, 2021 16:00