Deflazacort.pptx

“DEFLAZACORT”
Search Of A Safe & Effective
Dissociated Glucocorticoid

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” (i.e., inhibits) &
not “Transactivation” should be as
effective as standard GCs with fewer side
effects
“DEFLAZACORT”
Such A Dissociated Glucocorticoid

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 an inactive prodrug which is converted rapidly
to the active metabolite 21-desacetyldeflazacort.
• 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

• Prednisolone : Deflazacort is 1:1.2
• Methylprednisone : Deflazacort is 1:1.5
DEFLAZACORT
Equipotency of dose

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
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 supportthe
benefit of Deflazacort compared withprednisone

DEFLAZACORT vs PREDNISONE
On BMD
0.8
0.84
0.82
0.75
0.8
0.85
BMD
(g/cm2) Base line
12 months
0.75
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

Blood Glucose Control
Parameters at 4 week Deflazacort Prednisone
Plasma Glucose (mg%) 139 169
Insulin Requirement (U/d) 29 47
Patients 10 insulin treated diabetics requiring steroid
treatment
Treatment Deflazacort : 30 mg/day
Prednisone : 25 mg/day
Duration 4 weeks
Bruno A et al. Arch Intern Med. 1987Apr;147(4):679-80.

Blood Glucose Control
8.5
8.81
10.71
11
10.5
10
9.5
9
8.5
8
7.5
7
Average Pretreatment
for DFZ & PDN
Deflazacort Prednisone
Hb
A1C
(%of
toal
Hb)
Conclusion : Deflazacort, should prove advantageous in insulin-
treated diabetics who require steroid treatment
Bruno A et al. Arch Intern Med. 1987Apr;147(4):679-80

DEFLAZACORT vs METHYLPREDNISONE
Effect on Growth
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
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

Effect on Growth

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 ChronicArthritis
• 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
Treatment
Deflazacort : 1.5 mg/kg/d
Prednisone : 1 mg/kg/d
Duration 12 weeks
Markham A et al.Drugs 50(2); 1995: 317-33

DEFLAZACORT
Acute Exacerbation of Chronic Asthma
71.5
76.1
84
82
80
78
76
74
72
70
68
66
The forced vital capacity increased significantly from 76.1 to 81.4%
(%
) Forced Vital Capacity
Base
81.4
End Point
81
Markham A et al.Drugs 50(2); 1995: 317-33

DEFLAZACORT
Clinical Trials
ENT

DEFLAZACORT
Allergic Rhinitis
ARIA pocket guidelines
Steroid Type of steroid Action Side effects Comments

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
Treatment
Deflazacort 1 mg/kg x 2D; 0.5 mg/kg x 4D; 0.25 mg/kg x 4D
Duration 10 days
Tosca MA et al. Pediatr Allergy Immunol. 2003 Jun;14(3):238-41.

DEFLAZACORT
Nasal Polyps
Cassano P et al Acta Otorhinolaryngol Ital. 1996 Aug; 16(4): 334-8
Patients 30
Steroid
Treatment
Deflazacort + Fluticasone propionate topical
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

DEFLAZACORT
Clinical Trials
Rheumatology & Orthopedics

DEFLAZACORT vs METHYL PREDNISOLONE
Rheumatoid Arthritis
Patients 20 of RA (10 in each group)
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

17.2 17.6
7.9
9.4
0
5
10
15
20
Deflazacort Methyl Prednisolone
Richie
index
Baseline
Endpoint
Reduction in Simple Joint Count
2.3 2.25
1.1 1.1
0
0.5
1
1.5
2
2.5
Deflazacort Methylprednisolone
hours
Baseline
Endpoint
Reduction in Pain

Reduction in Morning Stiffness Improvement in Grip Strength
65
73.5
29.5
38
80
70
60
50
40
30
20
10
0
hours
Baseline
Endpoint
64.5
70.5
105.5
99
0
20
40
60
80
100
120
mm
Hg
Baseline
Endpoint

DEFLAZACORT vs PREDNISOLONE
In Patients With Chronic Inflammatory Disorders
Patients 26 (17 RA + 4 Polymyalgia Rheumatica + 2 Eczema +
3 Mixed connective tissue disease)
Prednisone : 20 mg/day
Duration 15 days & then titrated till 90 days
Gray RES et al. Arthritis & Rheumatism 1991; 34(3): 287-295

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

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

Broyer M et al. Pediatric Nephrol 1997; 11: 418-422
Outcomes:
Prednisolone
3.9 kg
More
Deflazacort
1.7kg
Less
Increase In body wt
Cushing’symptoms
Conclusion : Deflazacort was more effective than prednisolone in
limiting relapses & with less side effects

Patients 29 with proteinuria > 3 g/24 hrs
Steroid
Treatment
Prednisone 80 mg/day & then tapered
Deflazacort 96 mg/day & then tapered
Duration 1 year
Olgaard K et al. Calcif Tissue Int 1992; 50: 490-497

Olgaard K et al. Calcif Tissue Int 1992; 50: 490-497
9.9
8
1.1 1.4
0
2
4
6
8
10
12
Grams
Baseline
Endpoint
Urinary Protein
5.3
2
0
1
2
3
4
5
6
Prednisone Deflazacort
%
Prednisone
Deflazacort
Bone Loss Per Year

Cochrane Review
Patients Pediatric Patients from 19 trials
Steroid
Treatment
Prednisone (1 mg/kg/d)
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 actingupon
the intramural ureteral tract, expulsion time is significantly shortened,
especially with Deflazacort + tamsulosin
Alfa-1 adrenergic receptors blockade by tamsulosin causes smooth musclecell
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
Clinical Trials
Renal Transplant

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 insulinsensitivity

Renal Transplant

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

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
Bell’s palsy

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

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, 1mg/kg
alternate days for 1 month, 16 patients
Duration 12 months

DEFLAZACORT
In Drug Resistant Epilepsy

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
– Fat
- Glucose
- 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”

Deflazacort.pptx

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Deflazacort.pptx