DeflazacortIntroductionGlucocorticoids are the most important and frequently used class of anti-inflammatory drugs, but 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 ofselectively 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. Deflazacort(DFZ) , an oxazolinederivative of prednisolone is a step in this direction.

Pharmacological Properties

Fig 1. Chemical structure of Deflazacort

DFZ, a D-ring substituted synthetic steroid ,was introduced in 1969 . Its anti-inflammatory and immunosuppressive effects have been used in treating various diseases and are comparable to other steroids. 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 across individual disease conditions.

Pharmacokinetics Orally administered deflazacort is well absorbed and is immediately

converted by plasma esterases to the pharmacologically active metabolite deflazacort-21-hydroxide (D 21-OH), which achieves peak plasma concentrations in 1.5 to 2 h. It is 40% protein bound and has no affinity for corticosteroid binding globulin (transcortin) and binds to plasma protein and blood cells instead, crossing the blood-brain barrier in very low concentrations. These pharmacokinetic and biochemical properties of deflazacort may prevent it from reaching the hypothalamic or pituitary circulation during the first years; however, after a long-term treatment, deflazacort levels could increase in the central nervous system and finally produce effects similar to other glucocorticoids. Its plasma elimination

half-life is 1.1 to 1.9 h. Elimination takes place primarily through the kidneys; 70% of the administered dose is excreted in the urine, and the remaining 30% is eliminated through the feces.

Preclinical safety data

Safety studies have been carried out in the rat, dog, mouse and monkey. Teratogenic effects demonstrated in rodents and rabbits are

typical of those caused by other glucocorticoids. Deflazacort was not found to be carcinogenic in the mouse, but studies in the rat produced

carcinogenic findings consistent with the findings obtained using other glucocorticoids.

Therapeutic Use• Duchenne dystrophy• Nephrotic syndrome• Juvenile idiopathic arthritis• Asthma• Renal transplant• Idiopathic thrombocytopenic purpura• Drug-resistant epilepsy of childhood• Other disorders :Published data in children, evaluating deflazacort in other commondisorders such as systemic lupus erythematosus (SLE), dermatomyositis,rheumatic carditis, various dermatological conditions, acute lymphoblasticleukaemia, and lymphoma continues to be sparse. Deflazacort wasgenerally as effective as the comparative drug, and more effective thanplacebo, in controlled trials.

Side Effect Profile

Deflazacort shares all side-effect profiles of prednisolone such as candidiasis, cataract, dyspepsia, peptic ulcer, drug psychosis, impaired glucose tolerance, growth retardation, hirsutism, hypertension, hypokalaemia, muscle weakness, osteoporosis, pathological fracture, steroid facies, and delayed wound healing. Of the limited studies in children, adverse effects commonly reported include cushingoid features, osteoporosis, weight gain, glucose intolerance and growth retardation. Children are more vulnerable to their side-effects, particularly to effects on growth and adrenal suppression

Osteoporosis:

Deflazacort proved to be less harmful to the cancellous bone thanprednisolone in the only prospective, comparative, long-termhistomorphometric study available to date. Research reveals that

OPG(Osteoprotegerin) and RANKL (receptor activator of NF-KB ligand)

areosteoblast-derived proteins, responsible for inhibition and

stimulation ofbone resorption respectively. Studies in adults have demonstrated

afavorable ratio of serum RANKL: OPG, implying a potentially lesserbone loss with deflazacort.

The available but limited clinical trials in children suggest that deflazacort has some bone-sparing action as compared to prednisolone (when measured in terms of a lesser decline in the whole body mineral density). In general deflazacort appears to have less effect than prednisone on urinary calcium excretion, serum osteocalcin levels and serum parathyroid hormone levels, parameters

implicated in the pathogenesis of corticosteroid-induced osteoporosis. In 3 studies conducted to evaluate its effects on bone mass/density deflazacort therapy was associated with a smaller loss of bone mass/density than prednisone.

Weight gain/obesity Trials comparing deflazacort and prednisolone

have suggested a lesser increase in weight not only in patients of Duchenne's muscular dystrophy but also in those with nephrotic syndrome and Juvenile Rheumatoid Arthritis and also in patients of the post-renal transplant state.

Growth retardation: Deflazacort therapy has been associated with a lesser decline in the growth velocity and an stature improved after one to two years.

Cushingoid symptoms

Broyer et al. and Ferraris et al., have documented that the Cushingoid features were less with deflazacort as compared to prednisolone.

Glucose intolerance

Even presence of the pursuing trials, the metabolic effects of deflazacort as compared to prednisolone in children are scanty, it appears to favour deflazacort by reporting favorable Insulin:Glucose ratio. Deflazacort 36mg administered 12 and 2 hours before oral glucose tolerance testing in volunteers with familial history of non insulin-dependent diabetes mellitus had less impact on glucose metabolism than prednisone 30mg.

Adrenal suppression: Wajchenberg et al suggested that deflazacort‘s action in suppressing cortisol was confined to the pituitary only while prednisolone was active on both, pituitary and adrenals. Published clinical trials in children comparing effect on the two glands are still awaited.

Pregnancy and Lactation

The ability of corticosteroids to cross the placenta varies with individual drugs; however, deflazacort does cross the placenta. As with all drugs, corticosteroids should only be prescribed when the benefits to the mother and child outweigh the risks. When corticosteroids are essential, however, patients with normal pregnancies may be treated as if they were in the non gravid state. No data are available for deflazacort as regards excretion in breast milk. Doses of up to 50 mg daily of deflazacort are unlikely to cause systemic effects in the infant. Infants of mothers taking higher doses

of this drug may have adrenal suppression, but the benefits of breastfeeding are likely to outweigh any theoretical risk.

Dosage and Administration

Deflazacort is less potent than prednisone and is usually administered in proportionally higher dosages on the basis of body weight. In general, studies designed to determine the dosage equivalence of deflazacort and prednisone found deflazacort to be 25% less potent than prednisone, a dosage ratio of 1:1.3.Six mg of deflazacort has approximately the same anti-inflammatory potency as 5 mg prednisolone or prednisone.

Dosage should be individually titrated according to diagnosis, severity of disease and patient response and tolerance. The lowest dose that will produce an acceptable response should be used .In more serious and life-threatening conditions, high doses of deflazacort may be needed.

When deflazacort is used for long term in relatively benign chronic diseases, the maintenance dose should be kept as low as possible. Dosage may be needed to increase during periods of stress or during exacerbation of illness. In patients with hepatic impairment; blood levels of deflazacort may be increased. In renal impairment, no special precautions are necessary other than those usually adopted in patients receiving glucocorticoid therapy.

Deflazacort withdrawal

In patients who received higher physiological doses of systemic corticosteroids (approximately 9 mg per day or equivalent) for more than 3 weeks, withdrawal should not be abrupt.

Dose reduction should be carried out largely based on possibility of relapse of the disease due to reduction of dose of corticosteroids. Clinical assessment of disease process might be needed during withdrawal. If the disease is unlikely to relapse on withdrawal of systemic corticosteroids, but there is uncertainty regarding HPA suppression, the dose of systemic corticosteroids can be reduced rapidly to physiological doses. Once a daily dose equivalent to 9 mg deflazacort is reached, dose reduction should be slower to allow the HPA-axis to recover.

Over dosage :Treatment is needed in cases of acute over

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