Identification

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Name
Deflazacort
Accession Number
DB11921
Type
Small Molecule
Groups
Approved, Investigational
Description

Deflazacort, also known as Emflaza, is a corticosteroid prodrug used as an agent to manage Duchenne Muscular Dystrophy (DMD). It is marketed by Marathon Pharmaceuticals and was approved in February 2017 by the FDA.14,Label

Duchenne Muscular Dystrophy is an inherited disorder resulting from mutations of the dystrophin gene, which is important for muscle function. This disease can cause serious muscle weakness and progressive breathing and cardiovascular disability, severely impacting patient quality of life and survival.3,4,15 This disease usually manifests by muscle weakness in early childhood followed by loss of the ability to walk (ambulation) as early as age 7.4

Deflazacort delays the onset of muscle related complications resulting from DMD6, prolonging the lives of children diagnosed with this disease and exerting less harmful effects on the bone health and weight than other steroid medications.5,7

Structure
Thumb
Synonyms
  • Deflazacort
External IDs
MDL 458 / MDL-458
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
EmflazaTablet36 mg/1OralPtc Therapeutics, Inc.2018-09-10Not applicableUs
EmflazaSuspension22.75 mg/1mLOralMarathon Pharmaceuticals2017-02-09Not applicableUs
EmflazaTablet36 mg/1OralMarathon Pharmaceuticals2017-02-09Not applicableUs
EmflazaTablet30 mg/1OralPtc Therapeutics, Inc.2018-09-10Not applicableUs
EmflazaTablet18 mg/1OralPtc Therapeutics, Inc.2018-09-10Not applicableUs
EmflazaTablet30 mg/1OralMarathon Pharmaceuticals2017-02-09Not applicableUs
EmflazaTablet18 mg/1OralMarathon Pharmaceuticals2017-02-09Not applicableUs
EmflazaSuspension22.75 mg/1mLOralPtc Therapeutics, Inc.2018-09-10Not applicableUs
EmflazaTablet6 mg/1OralPtc Therapeutics, Inc.2018-09-10Not applicableUs
EmflazaTablet6 mg/1OralMarathon Pharmaceuticals2017-02-09Not applicableUs
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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International/Other Brands
Calcort (Shire) / Cortax / Decortil / Deflanil / MOAID / Xalcort (Beacon Pharmaceuticals Limited) / Zamen
Categories
UNII
KR5YZ6AE4B
CAS number
14484-47-0
Weight
Average: 441.524
Monoisotopic: 441.215137722
Chemical Formula
C25H31NO6
InChI Key
FBHSPRKOSMHSIF-GRMWVWQJSA-N
InChI
InChI=1S/C25H31NO6/c1-13-26-25(20(30)12-31-14(2)27)21(32-13)10-18-17-6-5-15-9-16(28)7-8-23(15,3)22(17)19(29)11-24(18,25)4/h7-9,17-19,21-22,29H,5-6,10-12H2,1-4H3/t17-,18-,19-,21+,22+,23-,24-,25+/m0/s1
IUPAC Name
2-[(1S,2S,4R,8S,9S,11S,12S,13R)-11-hydroxy-6,9,13-trimethyl-16-oxo-5-oxa-7-azapentacyclo[10.8.0.0²,⁹.0⁴,⁸.0¹³,¹⁸]icosa-6,14,17-trien-8-yl]-2-oxoethyl acetate
SMILES
[H][C@@]12C[C@@]3([H])[C@]4([H])CCC5=CC(=O)C=C[C@]5(C)[C@@]4([H])[C@@]([H])(O)C[C@]3(C)[C@@]1(N=C(C)O2)C(=O)COC(C)=O

Pharmacology

Indication

Deflazacort is indicated for the treatment of Duchenne Muscular Dystrophy (DMD) in patients 2 years of age and older.Label

Associated Conditions
Pharmacodynamics

Deflazacort exerts anti-inflammatory activity in DMD, likely improving various symptoms, including muscle weakness and cardiorespiratory symptoms in addition to delaying their onset.6 This allows for an increased quality of life and prevents the necessity for surgical procedures, such as those for scoliosis, which is associated with DMD. Studies showed significant preservation of muscle mass in patients generally treated with 0.9 mg/kg/day of deflazacort compared to a control group. The following findings are based on clinical studies using deflazacort on a long term basis6,8:

Effects on muscle strength

At age 16, individuals treated with long-term deflazacort had 63 ± 4% score in muscle strength compared to a mean muscle strength score of 31 ± 3% for control patients6. Significant improvements in climbing stairs and rising from a supine position were also seen in patients taking deflazacort.6

Effects on ambulation

Ambulation was significantly higher by 12 years of age and 18 years of age in patients taking deflazacort when compared with the control group. The control group showed a mean loss of ambulation of 2 years sooner than with deflazacort treatment.8

Effects on cardiac function

Mean left ventricular ejection fraction (a measure of cardiac function) was higher in patients treated with deflazacort over the long term. Preservation of cardiac function was demonstrated by a mean difference in ejection fraction of about 7%, favoring study groups taking deflazacort over control groups.8

Effects on spinal alignment

Children treated with deflazacort also significantly lowered the rate and severity of scoliosis and eliminated the need for scoliosis surgery after long-term treatment.6,8

Mechanism of action

Deflazacort is a corticosteroid prodrug with an active metabolite, 21-deflazacort, which binds to the glucocorticoid receptor to exert anti-inflammatory and immunosuppressive effects on the body.1,9,10 The exact mechanism by which deflazacort exerts its therapeutic effects in patients with DMD is unknown but likely occurs via its anti-inflammatory activities.Label

TargetActionsOrganism
UGlucocorticoid receptor
agonist
Humans
Additional Data Available
Adverse Effects

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Additional Data Available
Contraindications

Structured data covering drug contraindications. Each contraindication describes a scenario in which the drug is not to be used. Includes restrictions on co-administration, contraindicated populations, and more.

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Blackbox Warnings

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Absorption

Deflazacort is rapidly absorbed after oral administration with peak concentration occurring within 1-2 hours.10,Label One pharmacokinetic study determined an AUC (area under the curve) of 280 ng/ml · h.1

The bioavailability of both the oral suspension and tablet are similar.Label In clinical studies, coadministration of deflazacort crushed with food or applesauce did not affect absorption or bioavailability.Label

Volume of distribution

One study determined the volume of distribution to be 204 ± 84 L.1

Protein binding

The protein binding of the active metabolite of deflazacort is approximately 40%.Label,12

Metabolism

After oral ingestion, deflazacort is deacetylated at position 21 by plasma esterases, producing the active metabolite 21-deflazacort.1,10,Label,16 21-deflazacort is then further metabolized by CYP3A4 to inactive metabolite products.Label,13 Deflazacort 21-OH metabolism is extensive. The metabolite of deflazacort-21-OH is deflazacort 6-beta-OH.13,16

Route of elimination

Urinary excretion is the major route of deflazacort elimination, accounting for about about 70% of the excreted dose.1 The remainder of the dose (about 30%) is excreted in the feces1. Elimination is almost completed by 24 hours post-dose.11 21-deflazacort makes up about 18% of the eliminated drug in the urine.Label

Half life

The half-life of deflazacort ranges from 1.1 to 1.9 h 1,16

Clearance

114 ±27 L/h, according to one noncompartmental pharmacokinetic study.1

The clearance of corticosteroids is enhanced in hypothyroid patients and increased in patients with hyperthyroidism. Dosing adjustments may be considered according to thyroid status.Label A study of corticosteroid clearance was performed in patients with a creatinine clearance of 15 mL/min or less, and determined that the active metabolite of deflazacort, 21-deflazacort was similar to that in patients with normal renal clearance.Label

Toxicity

The LD50 for the oral dose is 5200 mg/kg (mouse); Oral TDLO (woman): 0.12 mg/kgMSDS

A note on altered endocrine function and immunosuppression

Deflazacort, as a steroid prodrug used over a long-term period, can cause hormone imbalance leading to diseases such as Cushing's Syndrome and hypothalamic-pituitary-adrenal axis suppression. It can also predispose to infection, as it promotes immunosuppression.10 It is important to monitor for hormonal imbalance and infection and provide necessary treatment if they occur.Label

Mutagenicity/carcinogenicity

Mutagenicity assays were negative in various laboratory and in vivo assays performed on rats.Label,16 Chronic use in mice for 2 years in one study resulted in a higher rate of osteoma and osteosarcomas in mice receiving 0.06, 0.12, 0.25, 0.50, or 1.0 mg/kg of deflazacort daily.Label

Use in pregnancy

There are no sufficient data to support the administration of deflazacort during pregnancy. Corticosteroid drugs such as deflazacort should only be used during pregnancy only if the benefits of therapy outweigh the potential risks.Label,16

Use in lactation

Corticosteroids, when administered systemically, are excreted in the breastmilk. Exposure may lead to disturbances in bone development and growth and endocrine disturbances in the exposed infant.Label,16

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

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe therapeutic efficacy of (R)-warfarin can be increased when used in combination with Deflazacort.
(S)-WarfarinThe therapeutic efficacy of (S)-Warfarin can be increased when used in combination with Deflazacort.
1-TestosteroneThe risk or severity of edema formation can be increased when 1-Testosterone is combined with Deflazacort.
16-BromoepiandrosteroneThe risk or severity of edema formation can be increased when 16-Bromoepiandrosterone is combined with Deflazacort.
19-norandrostenedioneThe risk or severity of edema formation can be increased when 19-norandrostenedione is combined with Deflazacort.
1alpha-Hydroxyvitamin D5The therapeutic efficacy of 1alpha-Hydroxyvitamin D5 can be decreased when used in combination with Deflazacort.
2-MethoxyethanolThe risk or severity of adverse effects can be increased when 2-Methoxyethanol is combined with Deflazacort.
2,4-thiazolidinedioneThe therapeutic efficacy of 2,4-thiazolidinedione can be decreased when used in combination with Deflazacort.
3,5-diiodothyropropionic acidThe therapeutic efficacy of 3,5-diiodothyropropionic acid can be decreased when used in combination with Deflazacort.
4-HydroxytestosteroneThe risk or severity of edema formation can be increased when 4-Hydroxytestosterone is combined with Deflazacort.
Additional Data Available
  • Extended Description
    Extended Description

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  • Severity
    Severity

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  • Evidence Level
    Evidence Level

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    Action

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Food Interactions
Not Available

References

General References
  1. Mollmann H, Hochhaus G, Rohatagi S, Barth J, Derendorf H: Pharmacokinetic/pharmacodynamic evaluation of deflazacort in comparison to methylprednisolone and prednisolone. Pharm Res. 1995 Jul;12(7):1096-100. [PubMed:7494809]
  2. Ding W, Ding L, Li WB, Pan H, Lin HD: [Pharmacokinetics of deflazacort tablets in healthy Chinese volunteers]. Yao Xue Xue Bao. 2014 Jun;49(6):921-6. [PubMed:25212041]
  3. Falzarano MS, Scotton C, Passarelli C, Ferlini A: Duchenne Muscular Dystrophy: From Diagnosis to Therapy. Molecules. 2015 Oct 7;20(10):18168-84. doi: 10.3390/molecules201018168. [PubMed:26457695]
  4. Gao QQ, McNally EM: The Dystrophin Complex: Structure, Function, and Implications for Therapy. Compr Physiol. 2015 Jul 1;5(3):1223-39. doi: 10.1002/cphy.c140048. [PubMed:26140716]
  5. Joshi N, Rajeshwari K: Deflazacort. J Postgrad Med. 2009 Oct-Dec;55(4):296-300. doi: 10.4103/0022-3859.58942. [PubMed:20083885]
  6. McAdam LC, Mayo AL, Alman BA, Biggar WD: The Canadian experience with long-term deflazacort treatment in Duchenne muscular dystrophy. Acta Myol. 2012 May;31(1):16-20. [PubMed:22655512]
  7. Ferraris JR, Pasqualini T, Legal S, Sorroche P, Galich AM, Pennisi P, Domene H, Jasper H: Effect of deflazacort versus methylprednisone on growth, body composition, lipid profile, and bone mass after renal transplantation. The Deflazacort Study Group. Pediatr Nephrol. 2000 Jul;14(7):682-8. [PubMed:10912543]
  8. Houde S, Filiatrault M, Fournier A, Dube J, D'Arcy S, Berube D, Brousseau Y, Lapierre G, Vanasse M: Deflazacort use in Duchenne muscular dystrophy: an 8-year follow-up. Pediatr Neurol. 2008 Mar;38(3):200-6. doi: 10.1016/j.pediatrneurol.2007.11.001. [PubMed:18279756]
  9. Campbell C, Jacob P: Deflazacort for the treatment of Duchenne Dystrophy: a systematic review. BMC Neurol. 2003 Sep 8;3:7. doi: 10.1186/1471-2377-3-7. Epub 2003 Sep 8. [PubMed:12962544]
  10. Parente L: Deflazacort: therapeutic index, relative potency and equivalent doses versus other corticosteroids. BMC Pharmacol Toxicol. 2017 Jan 5;18(1):1. doi: 10.1186/s40360-016-0111-8. [PubMed:28057083]
  11. Assandri A, Buniva G, Martinelli E, Perazzi A, Zerilli L: Pharmacokinetics and metabolism of deflazacort in the rat, dog, monkey and man. Adv Exp Med Biol. 1984;171:9-23. [PubMed:6372406]
  12. Nayak S, Acharjya B: Deflazacort versus other glucocorticoids: a comparison. Indian J Dermatol. 2008;53(4):167-70. doi: 10.4103/0019-5154.44786. [PubMed:19882026]
  13. Deshmukh R, Sharma L, Tekade M, Kesharwani P, Trivedi P, Tekade RK: Force degradation behavior of glucocorticoid deflazacort by UPLC: isolation, identification and characterization of degradant by FTIR, NMR and mass analysis. J Biomed Res. 2016 Mar;30(2):149-161. doi: 10.7555/JBR.30.20150074. Epub 2016 Feb 20. [PubMed:28276670]
  14. FDA approval information [Link]
  15. Duchenne Muscular Dystrophy organization page [Link]
  16. Calcort 6mg tablets, Medicines UK [Link]
External Links
KEGG Drug
D03671
PubChem Compound
189821
PubChem Substance
347828252
ChemSpider
164861
ChEBI
135720
ChEMBL
CHEMBL1201891
Wikipedia
Deflazacort
ATC Codes
H02AB13 — Deflazacort
MSDS
Download (24.1 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedBasic ScienceDuchenne's Muscular Dystrophy (DMD)1
1CompletedBasic ScienceHepatic Impairment1
1CompletedBasic ScienceImpaired Renal Function1
1CompletedOtherHealthy Volunteers1
1CompletedTreatmentDuchenne's Muscular Dystrophy (DMD)1
1CompletedTreatmentHealthy Volunteers1
2, 3CompletedTreatmentDysferlinopathy / LGMD2B / Miyoshi Myopathy1
3Active Not RecruitingTreatmentDuchenne's Muscular Dystrophy (DMD)1
3Not Yet RecruitingTreatmentLimb-Girdle Muscular Dystrophies1
3WithdrawnTreatmentDuchenne's Muscular Dystrophy (DMD)1
Not AvailableApproved for MarketingNot AvailableDuchenne's Muscular Dystrophy (DMD)1
Not AvailableRecruitingNot AvailableIgA Nephropathy / Immunosuppressive Treatment / Proteinuria in Nephrotic Range1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
SuspensionOral22.75 mg/1mL
TabletOral18 mg/1
TabletOral30 mg/1
TabletOral36 mg/1
TabletOral6 mg/1
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)>215 Chttps://www.trc-canada.com/product-detail/?D228975
water solubility108 μg/mLhttps://pdfs.semanticscholar.org/1eb8/8a36cea3d298d2253b27bb1a03f829871dac.pdf
logP2.4https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208684,208685Orig1s000ClinPharmR.pdf
pKa5.52https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208684,208685Orig1s000ClinPharmR.pdf
Predicted Properties
PropertyValueSource
Water Solubility0.0175 mg/mLALOGPS
logP2.56ALOGPS
logP1.8ChemAxon
logS-4.4ALOGPS
pKa (Strongest Acidic)14.74ChemAxon
pKa (Strongest Basic)0.48ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area102.26 Å2ChemAxon
Rotatable Bond Count4ChemAxon
Refractivity117.12 m3·mol-1ChemAxon
Polarizability46.79 Å3ChemAxon
Number of Rings5ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
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 gluco/mineralocorticoids, progestogins and derivatives. These are steroids with a structure based on a hydroxylated prostane moiety.
Kingdom
Organic compounds
Super Class
Lipids and lipid-like molecules
Class
Steroids and steroid derivatives
Sub Class
Pregnane steroids
Direct Parent
Gluco/mineralocorticoids, progestogins and derivatives
Alternative Parents
20-oxosteroids / 11-beta-hydroxysteroids / 3-oxo delta-1,4-steroids / Delta-1,4-steroids / Alpha-acyloxy ketones / Oxazolines / Secondary alcohols / Imidoesters / Cyclic ketones / Cyclic alcohols and derivatives
show 9 more
Substituents
Progestogin-skeleton / 20-oxosteroid / 3-oxo-delta-1,4-steroid / 3-oxosteroid / Hydroxysteroid / Oxosteroid / 11-beta-hydroxysteroid / 11-hydroxysteroid / Delta-1,4-steroid / Alpha-acyloxy ketone
show 24 more
Molecular Framework
Aliphatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Agonist
General Function
Zinc ion binding
Specific Function
Receptor for glucocorticoids (GC). Has a dual mode of action: as a transcription factor that binds to glucocorticoid response elements (GRE), both for nuclear and mitochondrial DNA, and as a modula...
Gene Name
NR3C1
Uniprot ID
P04150
Uniprot Name
Glucocorticoid receptor
Molecular Weight
85658.57 Da
References
  1. Mollmann H, Hochhaus G, Rohatagi S, Barth J, Derendorf H: Pharmacokinetic/pharmacodynamic evaluation of deflazacort in comparison to methylprednisolone and prednisolone. Pharm Res. 1995 Jul;12(7):1096-100. [PubMed:7494809]
  2. FDA label, Deflazacort [Link]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Yes
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. Yu J, Petrie ID, Levy RH, Ragueneau-Majlessi I: Mechanisms and Clinical Significance of Pharmacokinetic-Based Drug-Drug Interactions with Drugs Approved by the U.S. Food and Drug Administration in 2017. Drug Metab Dispos. 2019 Feb;47(2):135-144. doi: 10.1124/dmd.118.084905. Epub 2018 Nov 15. [PubMed:30442649]
  2. Deflazacort FDA label [Link]

Drug created on October 20, 2016 15:00 / Updated on June 19, 2019 12:58