“DEFLAZACORT”

Search Of A Safe & Effective

Dissociated Glucocorticoid

Prof.(Dr.) Annasaheb. J. Dhumale.

Head of Department of Medicine,
Chief Medical Oncologist & Haematologist,
Shri Shankaracharya Institute of Medical Sciences (SSIMS)
Bhilai (C.G).INDIA.PIN-490020
drajdhumale@gmail.com
 CORTICOSTEROID
• Glucocorticoids are the most important and
frequently used class of anti-inflammatory &
immunosuppressive drugs.

• It is used to treat a number of conditions like:

Asthma, Rheumatoid arthritis, Severe allergies…

• It was first used in clinical practice in 1949 for

the treatment of Rheumatoid arthritis.
 CORTICOSTEROID

• The currently available ones impair many healthy

anabolic processes warranting caution during both
short-term and long-term use.
• Research has been focused on elaboration of
selectively acting novel oral steroid that possess the
same efficacy in conditions for which they are used
today but with reduction in one or more of the dose-
limiting side effects.
A DISSOCIATED GLUCOCORTICOID
Dissociated Therapeutic Effects from Side Effects

Drugs that preferentially induce

“Transrepression” &
not “Transactivation”
should be as effective as standard
GCs with fewer side effects
“DEFLAZACORT”
Such A Dissociated Glucocorticoid
 Deflazacort -Side Effect Profile
Deflazacort shares all side-effect profiles of prednisolone such as:

• candidiasis, • hypertension,
• cataract, • hypokalaemia,
• dyspepsia, peptic ulcer, • muscle weakness,
• drug psychosis, • osteoporosis,
• growth retardation, • pathological fracture,
• hirsutism, • steroid facies, and
• impaired glucose • delayed wound healing.
tolerance,
 DEFLAZACORT
A Dissociated Glucocorticoid

Similar in efficacy as conventional GCs

• Anti-inflammatory
• Immunosuppressive
With less metabolic side effects
• Osteoporosis
• Diabetes/ Impaired GTT
• Cushing’s Syndrome
• Growth Retardation
• Skin atrophy
• Hypertension
 DEFLAZACORT
Clinical Pharmacology

• Deflazacort is a prodrug, which is converted rapidly to

the active metabolite.
• Deflazacort is a synthetic derivative of prednisolone
• Cmax (of 21-desacetyldeflazacort) = 116 ng/ml
• Tmax = 1.3 h : AUC = 280 ng/ml.h
• Terminal half-life = 1.3 h
• Elimination : 70% renal + 30% hepatic
 DEFLAZACORT
Deflazacort 6 mg is equivalent to:

Prednisolone………………..5 mg
Methylprednisolone………...4 mg
Betamethasone……………..750 mcg
Dexamethasone………….....750 mcg
Hydrocortisone………………20 mg
Cortisone acetate……………25 mg
Triamcinolone………………..4 mg
 DEFLAZACORT
Equipotency of dose

• Prednisolone : deflazacort is 1:1.2

• Methylprednisone : deflazacort is 1:1.5
 DEFLAZACORT
A Faster Corticosteroid

Onset time and onset of action are dependent upon tmax.

Pharm Res. 1995 Jul;12(7):1096-100.

DEFLAZACORT
A Potent Corticosteroid
DEFLAZACORT
A Safer Corticosteroid

Drugs. 1995 Aug;50(2):317-33

DEFLAZACORT
Safety
 DEFLAZACORT
Bone Sparing Action

• Compared with prednisone or betamethasone,

Deflazacort causes-
– a smaller decrease in intestinal calcium absorption
– less renal calcium excretion

• Studies on bone mineral density also support the

benefit of Deflazacort compared with prednisone
 DEFLAZACORT vs PREDNISONE
On BMD
0.85 0.84 Base line
0.82
0.8
0.8 12 months

0.75
0.75
BMD (g/cm2)

0.7

0.65

0.6

0.55

0.5
Deflazacort Prednisolone

Outcome
At 1 year, patients taking Deflazacort showed increase in BMD while
those taking prednisolone showed marked drop in BMD
Messina OD et al. J Rheumatol 1992; 19: 1520-6
 DEFLAZACORT vs PREDNISONE
Blood Glucose Control

Patients 10 insulin treated diabetics requiring steroid

treatment
Treatment Deflazacort : 30 mg/day
Prednisone : 25 mg/day
Duration 4 weeks

Parameters at 4 week Deflazacort Prednisone

Plasma Glucose (mg%) 139 169

Insulin Requirement (U/d) 29 47

Bruno A et al. Arch Intern Med. 1987 Apr;147(4):679-80.

 DEFLAZACORT vs PREDNISONE
Blood Glucose Control
11 10.71
10.5
Hb A1C (%of toal Hb)

10

9.5
9 8.81
8.5
8.5
8

7.5
7
Average Pretreatment Deflazacort Prednisone
for DFZ & PDN

Conclusion : Deflazacort, should prove advantageous in insulin-

treated diabetics who require steroid treatment
Bruno A et al. Arch Intern Med. 1987 Apr;147(4):679-80
 DEFLAZACORT vs METHYLPREDNISONE
Effect on Growth

Design Prospective, open, randomized, parallel group

study on 31 prepubertal renal transplant patients
Treatment Deflazacort : 0.30 mg/kg/day, 15 patients
methylprednisone : 0.20 mg/day, 16 patients
Duration 36 months
Ferraris et al. pediatr nephrol (2007) 22: 734-741

Conclusion: Deflazacort therapy might improve linear growth and lean body mass
and prevent excessive bone loss and fat accumulation. It also leads to an improvement
in lipoprotein profile without reduction in insulin sensitivity
 DEFLAZACORT vs METHYLPREDNISONE
Effect on Growth

Ferraris et al. pediatr nephrol (2007) 22: 734-741

 DEFLAZACORT
Sparing Effect on Growth & Skeletal Maturation

In spite of large intra-individual and inter-individual

variability, Deflazacort has a lower negative impact on
indicators of growth* than prednisolone
* e.g., height, statural age, skeletal age and body weight velocities
(i.e. the increase/year)

Aicardi G et al. Br J Rheumatol. 1993 May;32 Suppl 2:39-43

 DEFLAZACORT
Dosage

• Doses of Deflazacort usually lie in the range

0.25-1.5 mg/kg once daily or in divided doses
– Juvenile chronic arthritis: The usual maintenance
dose is between 0.25-1.0 mg/kg/day
– Nephrotic syndrome: Initial dose of usually 1.5
mg/kg/day followed by down titration according to
clinical need
– Bronchial asthma: The initial dose should be
between 0.25 - 1.0 mg/kg Deflazacort on alternate
days.
 DEFLAZACORT
Withdrawal

• In patients who have reached approximately 9 mg per

day dose of deflazacort for greater than 3 weeks,
withdrawal should not be abrupt

• Withdrawal should be slow in patients receiving doses

greater than 48 mg daily of deflazacort
 DEFLAZACORT
Safety

• Well tolerated in long term studies up to 4-5 years

 DEFLAZACORT
Usage (Indications)

• Asthma/ COPD
• Sarcoidosis/ ILD
• Nephrotic syndrome
• Renal transplantation
• RA & Juvenile Chronic Arthritis
• Allergies
• SLE
• Pemphigus, Lichen Planus
 DEFLAZACORT
Clinical Trials

Chest Medicine & Allergy

 DEFLAZACORT
Acute Exacerbation of Chronic Asthma

Patients 29, with >=40% reduction in FEV1

Steroid Deflazacort : 1.5 mg/kg/d
Treatment Prednisone : 1 mg/kg/d
Duration 12 weeks

Markham A et al.Drugs 50(2); 1995: 317-33

 DEFLAZACORT
Acute Exacerbation of Chronic Asthma

Forced Vital Capacity

Base End Point
84
81.4 81
82
80
78 76.1
76
(%)

74
71.5
72
70
68
66
Deflazacort Prednisone

The forced vital capacity increased significantly from 76.1 to 81.4%

Markham A et al.Drugs 50(2); 1995: 317-33

DEFLAZACORT
Clinical Trials

ENT
 DEFLAZACORT
Allergic Rhinitis

Steroid Type of steroid Action Side effects Comments

ARIA pocket guidelines

 DEFLAZACORT
Allergy

• Deflazacort & its active metabolite 21-desacetyl-

deflazacort have stronger anti-allergic effects
than prednisolone as evidenced by inhibition of
– passive cutaneous anaphylaxis
– arthus reaction
– delayed type of hypersensitivity

Omote M et al. Arzneim-Forsch/Drug Res 1994; 44(1): 149-153

 DEFLAZACORT
Allergic & Non-allergic Chronic Rhinosinusitis

Background : Predominant Th2 pattern (characterized by

antibody production) reported in allergic and nonallergic
chronic rhinosinusitis in asthmatic children

Patients 30 (16 allergic/14 non-allergic) asthmatic children (9 yrs)

Steroid Deflazacort 1 mg/kg x 2D; 0.5 mg/kg x 4D; 0.25 mg/kg x 4D

Treatment
Duration 10 days

Tosca MA et al. Pediatr Allergy Immunol. 2003 Jun;14(3):238-41.

 DEFLAZACORT
Nasal Polyps

Patients 30

Steroid Deflazacort + Fluticasone propionate topical

Treatment
Duration 24 months

Conclusion: High tolerability in all patients and to the high

percentage of good and very good short and medium term results were
obtained

Cassano P et al Acta Otorhinolaryngol Ital. 1996 Aug; 16(4): 334-8

 DEFLAZACORT
Clinical Trials

Rheumatology & Orthopedics

DEFLAZACORT vs METHYL PREDNISOLONE
Rheumatoid Arthritis

Patients 20 of RA (10 in each group)

Treatment Deflazacort : 30 mg/day
Methylprednisolone : 16 mg/day
Paracetamol as needed (No DMARDs/ NSAIDs)
Duration 6 months
Outcome :
Deflazacort & Methylprednisolone significantly reduced simple
joint count, pain & morning stiffness while improved grip strength

Auteri A et al. Int J Immunother 1994; X(2): 67-75

 DEFLAZACORT vs METHYL PREDNISOLONE
Rheumatoid Arthritis

Reduction in Simple Joint Count Reduction in Pain

20 Baseline 2.5 Baseline

17.6 2.3 2.25
17.2 Endpoint Endpoint
2
15
Richie index

1.5

hours
10 9.4
7.9 1.1 1.1
1

5
0.5

0 0
Deflazacort Methyl Prednisolone Deflazacort Methylprednisolone

Auteri A et al. Int J Immunother 1994; X(2): 67-75

 DEFLAZACORT vs METHYL PREDNISOLONE
Rheumatoid Arthritis

Reduction in Morning Stiffness Improvement in Grip Strength

80 120 Baseline
73.5
Baseline 105.5
70 Endpoint 99
65
Endpoint 100
60

50 80 70.5
64.5
hours

mm Hg
38
40
60
29.5
30
40
20

10 20
0
Deflazacort Methylprednisolone 0
Deflazacort Methylprednisolone

Auteri A et al. Int J Immunother 1994; X(2): 67-75

 DEFLAZACORT vs PREDNISOLONE
In Patients With Chronic Inflammatory Disorders

Patients 26 (17 RA + 4 Polymyalgia Rheumatica + 2 Eczema +

3 Mixed connective tissue disease)

Treatment Deflazacort : 24 mg/day

Prednisone : 20 mg/day

Duration 15 days & then titrated till 90 days

Gray RES et al. Arthritis & Rheumatism 1991; 34(3): 287-295

 DEFLAZACORT vs PREDNISOLONE
In Patients With Chronic Inflammatory Disorders

Conclusion :
• Deflazacort is an effective anti-inflammatory corticosteroid
with lesser side effects than prednisone in stimulating daily
calcium loss & in inhibiting endogenous cortisol secretion

• Thus Deflazacort may be better tolerated for longer

periods of time in patients with chronic inflammatory
conditions requiring glucocorticoid treatment

Gray RES et al. Arthritis & Rheumatism 1991; 34(3): 287-295

DEFLAZACORT
Clinical Trials

Nephrology
 DEFLAZACORT vs PREDNISOLONE
In Patients With Nephrotic Syndrome

Patients 40 children (20 in each group) of steroid dependent

idiopathic nephrotic syndrome

Steroid Treatment Deflazacort / Prednisone dosage as calculated by

equipotency ratio = 0.8

Duration 1 year

Follow-up 5.5 yrs

Broyer M et al. Pediatric Nephrol 1997; 11: 418-422

 DEFLAZACORT vs PREDNISOLONE
In Patients With Nephrotic Syndrome

Outcomes:
Prednisolone Deflazacort
Increase In body wt 3.9 kg 1.7kg
Cushing’symptoms More Less

Conclusion : Deflazacort was more effective than prednisolone in

limiting relapses & with less side effects

Broyer M et al. Pediatric Nephrol 1997; 11: 418-422

 DEFLAZACORT vs PREDNISOLONE
In Patients With Nephrotic Syndrome

Patients 29 with proteinuria > 3 g/24 hrs

Steroid Prednisone 80 mg/day & then tapered

Treatment Deflazacort 96 mg/day & then tapered
Duration 1 year

Olgaard K et al. Calcif Tissue Int 1992; 50: 490-497

 DEFLAZACORT vs PREDNISOLONE
In Patients With Nephrotic Syndrome

Urinary Protein Bone Loss Per Year

6
12 5.3
9.9 Baseline 5 Prednisone
10
Endpoint Deflazacort
8 4
8
Grams

%
3
6
2
2
4

1.4 1
2 1.1

0 0
Deflazacort Prednisone Prednisone Deflazacort

Olgaard K et al. Calcif Tissue Int 1992; 50: 490-497

 Cochrane Review
DEFLAZACORT vs PREDNISOLONE
In Patients With Nephrotic Syndrome

Patients Pediatric Patients from 19 trials

Steroid Prednisone (1 mg/kg/d)
Treatment Deflazacort (1.2 mg/kg/d)
Duration 1-2 years

Outcomes:
• Deflazacort was significantly more effective in maintaining
remission than prednisone in children who frequently relapsed
• There was no increase in adverse events

Hodson M et al. The Cochrane Database of Systematic Reviews 2005, Issue 1. Art. No.: CD001533
DEFLAZACORT
Clinical Trials

Urology
 DEFLAZACORT + TAMSULOSIN
For Ureteric Stone Expulsion After ESWL
Patients 98 (lower ureteric stones of > 5mm)
Treatment 4 groups
1= Control; 2= DFZ; 3 = TAM; 4 = DFZ + TAM
Deflazacort : 6 mg/day
Tamsulosin : 0.4 mg/day
Duration 5-7 days

Conclusion : When ESWL is associated with adjuvant therapy acting upon

the intramural ureteral tract, expulsion time is significantly shortened,
especially with Deflazacort + tamsulosin
Alfa-1 adrenergic receptors blockade by tamsulosin causes smooth muscle cell
relaxation of ureter & Deflazacort reduces edema
DEFLAZACORT
Clinical Trials

Pediatrics
 DEFLAZACORT
Moderate Acute Asthma in Children

Conclusion :
Deflazacort & Prednisolone show similar efficacy in improving pulmonary
function & in producing clinical improvement

Gartner S et al. An Pediatr (Barc) 2004; 61(3): 207-12

 DEFLAZACORT vs PREDNISOLONE
In Patients With Nephrotic Syndrome

Urinary Protein Bone Loss Per Year

6
12 5.3
9.9 Baseline 5 Prednisone
10
Endpoint Deflazacort
8 4
8
Grams

%
3
6
2
2
4

1.4 1
2 1.1

0 0
Deflazacort Prednisone Prednisone Deflazacort

Olgaard K et al. Calcif Tissue Int 1992; 50: 490-497

DEFLAZACORT
Clinical Trials

Renal Transplant
 DEFLAZACORT vs METHYLPREDNISONE
Renal Transplant

Design Prospective, open, randomized, parallel group

study on 31 prepubertal renal transplant patients
Treatment Deflazacort : 0.30 mg/kg/day, 15 patients
methylprednisone : 0.20 mg/day, 16 patients
Duration 36 months

Conclusion: Deflazacort therapy might improve linear growth and lean body mass
and prevent excessive bone loss and fat accumulation. It also leads to an improvement
in lipoprotein profile without reduction in insulin sensitivity

Ferraris et al. pediatr nephrol (2007) 22: 734-741

 DEFLAZACORT vs METHYLPREDNISONE
Renal Transplant

Ferraris et al. pediatr nephrol (2007) 22: 734-741

DEFLAZACORT
Clinical Trials

Dermatology
 DEFLAZACORT
In Pemphigus Vulgaris

• Deflazacort + azathioprine reported to be a preferred

therapy for pemphigus vulgaris

• Esophageal involvement in 67.8% pts. which normalized

with deflazacort therapy

Galloro G et al. Digest Liver Dis 2005; 37(3): 195-199

Mignogna MD et al. J Oral Pathol Med. 2000 Apr;29(4):145-52.
DEFLAZACORT
Clinical Trials

Neurology
 DEFLAZACORT
Bell’s palsy

Patients 47 with Idiopathic Facial (Bell’s) Palsy

Treatment Inj. Prednisolone 60 mg IM followed by equipotent
dose deflazacort (72 mg) which was tapered off
Duration One year
Outcome
• Improvement observed in <5 months
• Complete cure (full recovery of facial motor function) in 95.6%

Conclusion : This study supports early steroid treatment in Bell’s

Palsy
Hurtado Garcia JF et al. Acta Otorrinolaringol Esp. 1997 Apr;48(3):177-81
 DEFLAZACORT
In DMD-An Update

• Deflazacort attenuates loss of dystrophic myofiber integrity

by up-regulating the activity of the calcineurin phosphatase
in calcineurin/NF-AT pathway & has prophylactic effect
• Deflazacort treatment can attenuate DMD progression,
extend ambulation, and maintain muscle strength
• Patients who had been receiving deflazacort for > 3 years
were more likely to have preserved cardiac function

St-Pierre SJ et al FASEB J. 2004 Dec;18(15):1937-9

 DEFLAZACORT
In DMD-An 8 years follow up

Patients 79 patients of DMD

Treatment Deflazacort : 0.9 mg/kg at beginning, mean dose:
0.69 ± 0.2 mg/kg, 37 patients
Untreated group: 42 patients
Duration 8 years

Conclusion : The overall Impact on quality of life appears positive

Sylvie Houde et al, Pediatric Neurology 2008, 38, 200-204

DEFLAZACORT
In DMD
 DEFLAZACORT
In Drug Resistant Epilepsy

Design Open, non blinded, randomized study on 35 children with

drug resistant epilepsy
Treatment Deflazacort : 0.75 mg/kg, 19 patients
Hydrocortisone: 10 mg/kg for 1 month, 5 mg/kg for 1 month,
2.5 mg/kg for 1 month, 1 mg/kg for 1 month, 1 mg/kg
alternate days for 1 month, 16 patients
Duration 12 months
 DEFLAZACORT
In Drug Resistant Epilepsy
SUMMARY
 DEFLAZACORT
Summary

• The options today to reduce side effects with GCs now

includes Deflazacort

• Deflazacort, a “dissociated” glucocorticoid, has desired

anti-inflammatory & immunomodulatory actions but with
negligible metabolic side effects on
– Bone - Glucose
– Fat - Suppression of HPA
– Mineralocorticoid activity - Affect on skeletal growth
DEFLAZACORT vs COVENTIONAL GCs
Clinical Benefits of The Second Generation GCs

• Equal efficacy with less side effects

• Bone sparing effect/ less osteoporosis
• Safe in children (does not affect growth velocity)
• Non-diabetogenic, so safe in diabetics
• Less cushingoid features, better compliance
• Patients may cope better to anesthetic/ surgical stress
(less HPA axis suppression)
• Safety in cardiovascular pts. (less sodium & water
retention)
 DEFLAZACORT
At the end

• Deflazacort has definite advantage in diabetics,

osteoporosis patients and in children ( nephrotics) likely
to require its long term use.
• Treatment with deflazacort may cause less serious
metabolic sequalae than treatment with prednisolone,
• Deflazacort should be generally reserved for the treatment
of patients predisposed to, or who develop intolerable
metabolic disease effects while on steroids.
 DEFLAZACORT
To Conclude

Hence,Deflazacort, a second generation

glucocorticoid, may
represent an important step towards
“Search for a Effective & Safe
Glucocorticoid”
Thank You