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Deferasirox
General information
Deferasirox (ICL670), a hydroxyphenyltriazole derivative, is a tridentate selective iron chelator and an N-substituted bis-hydroxyphenyltriazole compound for oral use, available as 125, 250, and 500 mg tablets and administered in a daily dose of 20–50 mg/kg. It is rapidly absorbed (about 70%), highly bound to albumin, has a plasma half-life of 11–19 hours, and probably undergoes enterohepatic recirculation [ ]. Two molecules of deferasirox form a stable complex with one iron Fe 3 + atom. Deferoxamine is mainly glucuronidated; about 84% is excreted in the feces and only about 8% in the urine. Excretion of the deferasirox–iron complex and its metabolites is probably mainly by hepatobiliary anion transport. At therapeutic doses induction and inhibition of cytochrome P450 enzymes have not been observed. A daily dose of 20–30 mg/kg successfully controls iron balance in many but not in all patients [ ]. In some patients with high transfusion burdens a higher dose may be needed to prevent rising serum ferritin concentrations and hepatic iron concentrations, two molecules of which form a stable complex with each iron atom.
There is increasing knowledge of the pharmacology of deferasirox and interest in its therapeutic use, in particular in non-hemolytic transfusion dependent anemias [ ]. Animal studies have suggested that the kidney is a potential target for adverse effects, but there is as yet no evidence of progressive renal damage. It also produces a dose dependent increase in β 2 microglobulin, typically transient, the clinical relevance of which is uncertain [ ]. Adverse events that have been recorded include headache, nausea, and diarrhea [ ]. In patients with myelodysplastic syndrome non-progressive changes in serum creatinine, gastrointestinal disturbances, and rashes have been reported [ ].
At the same time, post-marketing reports have raised concerns about the possible occurrence of serious adverse reactions, such as anaphylaxis, gastrointestinal ulceration and hemorrhage, neurosensory hearing loss, lenticular opacities, acute renal insufficiency, liver damage, agranulocytosis, and thrombocytopenia [ , , ]. However, detailed information is sparse, and there is an urgent need for clarification of the current uncertainty. It is possible that deferasirox can damage various organs, especially the kidneys, by increasing iron absorption and de-compartmentalizing chelated iron in these tissues [ ].
Drug studies
Comparative studies
In a multinational phase III trial in 65 clinical centers in 12 counties, with the primary aim of investigating the hypothesis that deferasirox is not inferior to deferoxamine, 586 patients were randomly allocated to deferasirox (n = 296) or deferoxamine (n = 290) [ ]. Depending on the iron load, deferasirox 5–10 mg/kg/day was given to patients with low liver iron content, 20 mg/kg/day to patients with moderate liver iron content, and 30 mg/kg/day to patients with high iron burdens requiring major reduction. For comparison, deferoxamine was given in doses of 20–35 mg/kg, 35–50 mg/kg, and 50 mg/kg and higher; the doses of deferoxamine were normalized to administration on 5 days a week. Most of the patients (541; 92.3%) completed a 1-year treatment course; 17 stopped using deferasirox and 12 stopped using deferoxamine. Both baseline and 1-year liver iron content were measured in 587 patients. The primary end-point (maintenance or reduction of liver iron content) was not met in the overall population, possibly owing to proportionately lower doses of deferasirox. Dosage adjustment, dosage interruption, and discontinuation combined were similar. A rash occurred in 11% of patients, 15% had gastrointestinal upsets (nausea, vomiting, abdominal pain, diarrhea, constipation; median duration 8 days or less), and in 38% there were mild increases in serum creatinine (less than twice the upper limit of normal and generally within the reference range), more frequently with high doses. Deafness (neurosensory deafness or hypoacusis) was reported in eight patents receiving deferasirox, but was considered to be drug related in only one, and in seven receiving deferoxamine, but considered to be drug related in five. In the deferasirox group cataracts or lenticular opacities were reported as adverse events in two patients, but considered to be drug related in only one, compared with seven of the patients on deferoxamine, and considered to be drug related in four. In neither group was there any case of agranulocytosis. One patient died suddenly of an unknown cause while using deferasirox.
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