Identification

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

Deflazacort is a glucocorticoid used as an anti-inflammatory and immunosuppressant. It was approved in February, 2017 by the FDA for use in treatment of Duchenne muscular dystrophy (trade name Emflaza).

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

is a corticosteroid indicated for the treatment of Duchenne muscular dystrophy (DMD) in patients 5 years of age and older

Associated Conditions
Pharmacodynamics

Clinical studies have indicated that the average potency ratio of deflazacort to prednisolone is 0.69–0.89 and 6 mg of deflazacort is equivalent to 5 mg of prednisolone. However, the therapeutic dosage ratio has been reported to range from 1:1.2 to 1:1.5 Due to the short pharmacokinetic half-life of its active metabolite, pharmacodynamic effects of deflazacort are of shorter duration than those of methylprednisolone and prednisolone.

Mechanism of action

Deflazacort is a corticosteroid prodrug, whose active metabolite, 21-desDFZ, acts through the glucocorticoid receptor to exert anti-inflammatory and immunosuppressive effects. The precise mechanism by which deflazacort exerts its therapeutic effects in patients with DMD is unknown.

Absorption

After oral administration in the fasted state, the median Tmax with deflazacort tablets or suspension is about 1 hour (range 0.25 to 2 hours). Food Effect: Co-administration of deflazacort tablets with a high-fat meal reduced Cmax by about 30% and delayed Tmax by one hour, relative to administration under fasting conditions, but there was no effect on the overall systemic absorption as measured by AUC. The administration of deflazacort with food or crushed in applesauce did not affect the absorption and bioavailability of deflazacort. Research findings: The pharmacokinetic parameters of 21-OH DFZ after the single oral administration of 6 mg, 12 mg and 24 mg DFZ tablets were as follows: (37.7 +/- 11.6), (61.5 +/- 17.7) and (123 +/- 23) ng x mL(-1) for C(max); (1.90 +/- 0.32), (1.96 +/- 0.27) and (2.13 +/- 0.34) h for t1/2; (96.6 +/- 25.9), (190 +/- 44) and (422 +/- 107) ng x h x mL(-1) for AUC(0-14 h), respectively. After the multiple dose administration, the mean plasma concentration at steady-state C(av) was (7.00 +/- 1.66) ng x mL(-1) and the degree of plasma concentration fluctuation DF was 7.7 +/- 1.2.

Volume of distribution

Not available

Protein binding

The protein binding of the active metabolite of deflazacort is about 40%.

Metabolism

Deflazacort is rapidly converted to the active metabolite 21-desDFZ by esterases after oral administration. 21-desDFZ is further metabolized by CYP3A4 to several other inactive metabolites.

Route of elimination

Urinary excretion is the predominant route of deflazacort elimination (about 68% of the dose), and the elimination is almost completed by 24 hours post dose. 21-desDFZ accounts for 18% of the eliminated drug in the urine.

Half life

half-life is 1.1 to 1.9 h

Clearance

Not available

Toxicity

The LD50 for the oral dose is greater than 4000 mg/kg in laboratory animals.

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 metabolism of 3,5-diiodothyropropionic acid can be decreased when combined with Deflazacort.
4-HydroxytestosteroneThe risk or severity of edema formation can be increased when 4-Hydroxytestosterone is combined with Deflazacort.
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. 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]
  3. 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]
  4. FDA label [Link]
External Links
KEGG Drug
D03671
PubChem Compound
189821
PubChem Substance
347828252
ChemSpider
164861
ChEBI
135720
ChEMBL
CHEMBL1201891
Wikipedia
Deflazacort
ATC Codes
H02AB13 — Deflazacort

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
3RecruitingTreatmentDuchenne'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
Not Available
Experimental Properties
Not Available
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

Enzymes

Kind
Protein
Organism
Human
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
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Substrate
General Function
Carboxylic ester hydrolase activity
Specific Function
Not Available
Gene Name
CES1A1a
Uniprot ID
Q6LAP9
Uniprot Name
Carboxylesterase
Molecular Weight
1908.25 Da

Drug created on October 20, 2016 15:00 / Updated on December 16, 2018 06:59