Deferasirox Chronic Iron Overload [1921

Country of origin Originator

Novartis US


First introduction Introduced by

Novartis Exjade

Trade name

CAS registry no Molecular weight

201530-41-8 373.4

Iron overload is a potentially life-threatening cumulative toxicity that occurs frequently in patients who receive multiple blood transfusions for the treatment of certain types of chronic anemias such as thalassemia and sickle-cell disease, as well as for the treatment of myelodysplastic syndromes. Progressive iron overload, if untreated, often causes injury to heart, liver, endocrine organs, joints, and other target cells and tissues. Iron overload is treated by administration of iron chel-ators, which mobilize the iron deposits into soluble complexes that can be excreted from the body. The current standard of care in iron chelation, deferoxamine (DesferalĀ®), is effective, but typically requires subcutaneous infusion lasting eight to twelve hours per day, for five to seven days a week for as long as the patient continues to receive blood transfusions. In many patients, the need for transfusion and chelation therapy may be life-long. This has resulted in low patient acceptance of the product. Deferipone is an orally available iron chelator that has been marketed in certain parts of the world; however, it has a short duration of action and may be associated with serious side effects. Deferasirox, launched last year, is the latest entry in iron chelation therapy. It is an orally active tridentate ligand that binds iron with high affinity in a 2:1 ratio. The recommended dosage is 20mg/kg of body weight once, daily. Deferasirox is synthesized in two steps starting from salicylamide, by first condensing with salicyloyl chloride to afford 2-(2-hydroxyphenyl)benz[1,3]oxazin-4-one, and subsequent reaction of this intermediate with 4-hydrazinobenzoic acid. Deferasirox is rapidly absorbed following oral administration, reaching peak plasma concentrations at 1.5-4 h. The Cmax and AUC increase approximately linearly with dose after both single administration and under steady-state conditions. Deferasirox is highly protein bound (~99%), almost exclusively to serum albumin. It has a volume of distribution at steady state of 14.37 + 2.69 L, mean elimination half-life ranging from 8 to 16 hours, and oral bioavailability of 70%. Glucuronidation is the main metabolic pathway for deferasirox, with minimal oxidative metabolism by CYP450 enzymes. Deferasirox and metabolites are primarily excreted in the feces via the bile (84% of the dose). Clinical trials involving more than 1000 adults and children demonstrated that deferasirox, at 20-30 mg/kg/day led to maintenance of or reductions in liver iron concentration, an indicator for body iron content in patients receiving blood transfusions. The most frequently reported adverse events were transient in nature and included mild to moderate nausea, vomiting, diarrhea, abdominal pain, and skin rash. In addition, patients treated with deferasirox experienced dose-related increase in serum creatinine at a greater frequency compared with defer-oxamine-treated patients (38% vs. 15%, respectively). However, most of the creatinine elevations remained within the normal range. As with deferoxamine injection, deferasirox was associated with a low incidence of ocular and auditory disturbances.

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