DeflazacortIntroductionGlucocorticoids are the most important and frequentlyused class of anti-inflammatory drugs, but the currentlyavailable ones impair many healthy anabolic processeswarranting caution during both short-term and longterm use. Research has been focused on elaboration ofselectively acting novel oral steroid that possess thesame efficacy in conditions for which they are usedtoday 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 PropertiesFig 1. Chemical structure of Deflazacort
DFZ, a D-ring substituted synthetic steroid ,wasintroduced in 1969 . Its anti-inflammatory andimmunosuppressive effects have been used intreating various diseases and are comparable toother steroids. Clinical studies have indicated thatthe average potency ratio of deflazacort toprednisolone is 0.69-0.89 and 6 mg of deflazacort isequivalent to 5 mg of prednisolone. However, thetherapeutic dosage ratio has been reported torange from 1:1.2 to 1:1.5 across individual diseaseconditions.
PharmacokineticsOrally administered deflazacort is well absorbed and isimmediately converted by plasma esterases to thepharmacologically active metabolite deflazacort-21-hydroxide (D21-OH), which achieves peak plasma concentrations in 1.5 to 2h. It is 40% protein bound and has no affinity for corticosteroidbinding globulin (transcortin) and binds to plasma protein andblood cells instead, crossing the blood-brain barrier in very lowconcentrations. These pharmacokinetic and biochemicalproperties of deflazacort may prevent it from reaching thehypothalamic or pituitary circulation during the first years;however, after a long-term treatment, deflazacort levels couldincrease in the central nervous system and finally produceeffects similar to other glucocorticoids. Its plasma eliminationhalf-life is 1.1 to 1.9 h. Elimination takes place primarily throughthe kidneys; 70% of the administered dose is excreted in theurine, and the remaining 30% is eliminated through the feces.
Preclinical safety dataSafety studies have been carried out in the rat, dog,mouse and monkey. Teratogenic effectsdemonstrated in rodents and rabbits aretypical of those caused by other glucocorticoids.Deflazacort was not found to be carcinogenic in themouse, but studies in the rat producedcarcinogenic findings consistent with the findingsobtained 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 ProfileDeflazacort shares all side-effect profiles ofprednisolone such as candidiasis, cataract,dyspepsia, peptic ulcer, drug psychosis, impairedglucose tolerance, growth retardation, hirsutism,hypertension, hypokalaemia, muscle weakness,osteoporosis, pathological fracture, steroid facies,and delayed wound healing. Of the limitedstudies in children, adverse effects commonlyreported include cushingoid features,osteoporosis, weight gain, glucose intoleranceand growth retardation. Children are morevulnerable to their side-effects, particularly toeffects on growth and adrenal suppression
Osteoporosis:Deflazacort proved to be less harmful to the cancellous bonethanprednisolone in the only prospective, comparative, long-termhistomorphometric study available to date. Research revealsthat OPG(Osteoprotegerin) and RANKL (receptor activator of NF-KBligand) areosteoblast-derived proteins, responsible for inhibition andstimulation ofbone resorption respectively. Studies in adults havedemonstrated afavorable ratio of serum RANKL: OPG, implying a potentiallylesserbone loss with deflazacort.
The available but limited clinical trials in childrensuggest that deflazacort has some bone-sparingaction as compared to prednisolone (whenmeasured in terms of a lesser decline in the wholebody mineral density). In general deflazacortappears to have less effect than prednisone onurinary calcium excretion, serum osteocalcin levelsand serum parathyroid hormone levels, parametersimplicated in the pathogenesis of corticosteroid-induced osteoporosis. In 3 studies conducted toevaluate its effects on bone mass/densitydeflazacort therapy was associated with a smallerloss of bone mass/density than prednisone.
Weight gain/obesityTrials comparing deflazacort and prednisolonehave suggested a lesser increase in weight notonly in patients of Duchennes muscular dystrophybut also in those with nephrotic syndrome andJuvenile Rheumatoid Arthritis and also in patientsof the post-renal transplant state.Growth retardation: Deflazacort therapy has beenassociated with a lesser decline in the growthvelocity and an stature improved after one to twoyears.
Cushingoid symptomsBroyer et al. and Ferraris et al., havedocumented that the Cushingoid featureswere less with deflazacort as compared toprednisolone.
Glucose intoleranceEven presence of the pursuing trials, the metabolic effects ofdeflazacort as compared to prednisolone in children arescanty, it appears to favour deflazacort by reporting favorableInsulin:Glucose ratio. Deflazacort 36mg administered 12 and 2hours before oral glucose tolerance testing in volunteers withfamilial history of non insulin-dependent diabetes mellitushad less impact on glucose metabolism than prednisone30mg.Adrenal suppression: Wajchenberg et al suggested thatdeflazacort‘s action in suppressing cortisol was confined tothe pituitary only while prednisolone was active onboth, pituitary and adrenals. Published clinical trials inchildren comparing effect on the two glands are still awaited.
Pregnancy and LactationThe ability of corticosteroids to cross the placenta varies withindividual drugs; however, deflazacort does cross theplacenta. As with all drugs, corticosteroids should only beprescribed when the benefits to the mother and childoutweigh the risks. When corticosteroids are essential,however, patients with normal pregnancies may be treated asif they were in the non gravid state. No data are available fordeflazacort as regards excretion in breast milk. Doses of up to50 mg daily of deflazacort are unlikely to cause systemiceffects in the infant. Infants of mothers taking higher dosesof this drug may have adrenal suppression, but the benefitsof breastfeeding are likely to outweigh any theoretical risk.
Dosage and AdministrationDeflazacort is less potent than prednisone and is usuallyadministered in proportionally higher dosages on the basisof body weight. In general, studies designed to determinethe dosage equivalence of deflazacort and prednisonefound deflazacort to be 25% less potent than prednisone,a dosage ratio of 1:1.3.Six mg of deflazacort hasapproximately the same anti-inflammatory potency as 5mg 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 responseshould be used .In more serious and life-threateningconditions, high doses of deflazacort may be needed.
When deflazacort is used for long term inrelatively benign chronic diseases, themaintenance dose should be kept as low aspossible. Dosage may be needed to increaseduring periods of stress or duringexacerbation of illness. In patients withhepatic impairment; blood levels ofdeflazacort may be increased. In renalimpairment, no special precautions arenecessary other than those usually adoptedin patients receiving glucocorticoid therapy.
Deflazacort withdrawalIn patients who received higher physiological doses ofsystemic corticosteroids (approximately 9 mg per day orequivalent) for more than 3 weeks, withdrawal should notbe abrupt.Dose reduction should be carried out largely based onpossibility of relapse of the disease due to reduction ofdose of corticosteroids. Clinical assessment of diseaseprocess might be needed during withdrawal. If the diseaseis unlikely to relapse on withdrawal of systemiccorticosteroids, but there is uncertainty regarding HPAsuppression, the dose of systemic corticosteroids can bereduced rapidly to physiological doses. Once a daily doseequivalent to 9 mg deflazacort is reached, dose reductionshould be slower to allow the HPA-axis to recover.
Over dosage :Treatment is needed in cases of acute overdosage is unlikely. The LD50 for the oral doseis greater than 4000 mg/kg in laboratoryanimals.