Identification

Name
Eliglustat
Accession Number
DB09039  (DB05715)
Type
Small Molecule
Groups
Approved
Description

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. Eliglustat was approved for use by the FDA in August 2014.

Structure
Thumb
Synonyms
  • 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
Product Ingredients
IngredientUNIICASInChI Key
Eliglustat tartrateN0493335P3928659-70-5KUBARPMUNHKBIQ-VTHUDJRQSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
CerdelgaCapsule84 mgOralSanofi Genzyme, a Division of Sanofi Aventis Canada Inc2017-07-26Not applicableCanada
CerdelgaCapsule84 mgOralGenzyme Europe Bv2015-01-19Not applicableEu
CerdelgaCapsule84 mgOralGenzyme Europe Bv2015-01-19Not applicableEu
CerdelgaCapsule84 mg/1OralGenzyme Corporation2014-09-03Not applicableUs
CerdelgaCapsule84 mgOralGenzyme Europe Bv2015-01-19Not applicableEu
Categories
UNII
DR40J4WA67
CAS number
491833-29-5
Weight
Average: 404.551
Monoisotopic: 404.267507647
Chemical Formula
C23H36N2O4
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]octanimidic acid
SMILES
[H][C@](CN1CCCC1)(N=C(O)CCCCCCC)[C@]([H])(O)C1=CC2=C(OCCO2)C=C1

Pharmacology

Indication

Eliglustat is indicated for the long-term treatment of type 1 Gaucher disease in patients who are CYP2D6 extensive metabolizers (EMs), intermediate metabolizers (IMs), or poor metabolizers (PMs) in treatment-naive and treatment-experienced adult patients.

Associated Conditions
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
Human
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).

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.

Affected organisms
  • Humans and other mammals
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
DrugInteraction
(R)-warfarinThe metabolism of Eliglustat can be decreased when combined with (R)-warfarin.
(S)-WarfarinThe metabolism of Eliglustat can be decreased when combined with (S)-Warfarin.
3,5-diiodothyropropionic acidThe metabolism of Eliglustat can be decreased when combined with 3,5-diiodothyropropionic acid.
4-hydroxycoumarinThe metabolism of Eliglustat can be decreased when combined with 4-hydroxycoumarin.
4-MethoxyamphetamineThe metabolism of 4-Methoxyamphetamine can be decreased when combined with Eliglustat.
5-androstenedioneThe metabolism of Eliglustat can be decreased when combined with 5-androstenedione.
6-Deoxyerythronolide BThe metabolism of Eliglustat can be decreased when combined with 6-Deoxyerythronolide B.
6-O-benzylguanineThe metabolism of Eliglustat can be decreased when combined with 6-O-benzylguanine.
AbemaciclibThe metabolism of Eliglustat can be decreased when combined with Abemaciclib.
AbexinostatThe risk or severity of QTc prolongation can be increased when Abexinostat is combined with Eliglustat.
Food Interactions
Not Available

References

General References
  1. Poole RM: Eliglustat: first global approval. Drugs. 2014 Oct;74(15):1829-36. doi: 10.1007/s40265-014-0296-3. [PubMed:25239269]
  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. [PubMed:17509920]
External Links
KEGG Drug
D09893
PubChem Compound
23652731
PubChem Substance
310264987
ChemSpider
28475348
ChEBI
82752
ChEMBL
CHEMBL2110588
PharmGKB
PA166123486
Wikipedia
Eliglustat
ATC Codes
A16AX10 — Eliglustat
AHFS Codes
  • 92:92.00 — Other Miscellaneous Therapeutic Agents
FDA label
Download (376 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedNot AvailableHealthy Volunteers1
1CompletedBasic ScienceHealthy Volunteers1
1CompletedTreatmentGaucher's Disease3
1CompletedTreatmentHealthy Volunteers1
2CompletedTreatmentCerebroside Lipidosis Syndrome / Gaucher Disease, Non-Neuronopathic Form / Gaucher Disease, Type 1 / Glucocerebrosidase Deficiency Disease / Glucosylceramide Beta-Glucosidase Deficiency Disease1
3CompletedTreatmentGaucher Disease, Type 12
3CompletedTreatmentGaucher's Disease1
3Enrolling by InvitationTreatmentGaucher's Disease1
3RecruitingTreatmentGaucher's Disease Type 1 / Gaucher's disease type III1
Not AvailableEnrolling by InvitationTreatmentGaucher Disease, Type III1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
CapsuleOral84 mg
CapsuleOral84 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US6916802No2005-07-122022-04-29Us
US7615573No2009-11-102022-04-29Us
US7196205No2007-03-272022-04-29Us
US7253185No2007-08-072022-04-29Us

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.038 mg/mLALOGPS
logP3.79ALOGPS
logP1.46ChemAxon
logS-4ALOGPS
pKa (Strongest Acidic)5.21ChemAxon
pKa (Strongest Basic)8.87ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count6ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area74.52 Å2ChemAxon
Rotatable Bond Count11ChemAxon
Refractivity114.28 m3·mol-1ChemAxon
Polarizability46 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

Taxonomy

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
Benzo-1,4-dioxane / Alkyl aryl ether / Aralkylamine / Fatty amide / N-acyl-amine / Para-dioxin / N-alkylpyrrolidine / Benzenoid / Fatty acyl / 1,3-aminoalcohol
show 23 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
secondary alcohol, carboxamide, N-alkylpyrrolidine, benzodioxine (CHEBI:82752)

Targets

Kind
Protein
Organism
Human
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. [PubMed:25239269]

Enzymes

Kind
Protein
Organism
Human
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. [PubMed:25239269]
Kind
Protein
Organism
Human
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. [PubMed:25239269]

Drug created on April 02, 2015 10:54 / Updated on November 17, 2018 07:23