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Orally Active Iron Chelator May be Effective in Treating Iron Overload

The orally active iron chelator ICL670 given once daily at 20 mg/kg seems to be effective and is reasonably well tolerated, according to the findings of a new study.

Patients with thalassaemia and others who require chronic red-blood-cell transfusions must receive chelation. The currently available chelator deferoxamine is effective but is must be administered intravenously. Another chelator, deferiprone, is orally active but is rapidly inactivated and hence has very low efficiency for iron chelation.

Eric Nisbet-Brown, MD, with the Department of Paediatrics, Harvard Medical School, Boston, Massachusetts, United States, and colleagues, investigated a novel orally active agent ICL670 (4-[3,5-bis(2-hydroxyphenyl)-1,2,4-triazol-1-yl]-benzoic acid), in 24 patients with beta-thalassaemia and transfusional iron overload. All patients were 16 years or older with serum ferritin values of between 1000 and 8000 ng/mL.

Patients consumed a diet with a defined content of iron, and 2 patients in each of 3 cohorts were randomly allocated placebo. Five or more patients from each cohort received 1 daily dose of ICL670 at 10, 20, or 40 mg/kg/day, from day 1 to 12. The researchers measured net iron excretion (NIE) between days 1 and 12.

They found that ICL670 was absorbed promptly and was detected in the blood for 24 hours. Compared to placebo, a linear relationship was recorded between exposure to ICL670 and total iron excretion (p<0·0001). All 3 doses appeared to be effective.

According to the researchers, the 20 mg/kg/day dose would prevent net iron accumulation in most patients transfused with 12 to 15 mL packed red-blood-cells/kg/month. Four patients showed signs of skin rashes at the 2 higher doses, and 1 patient developed grade 2 transaminitis. "We did not detect any systemic toxic manifestations of the drug," the authors note.

The researchers point out that this is a short-term study that "shows only early evidence of efficacy and absence of serious toxic effects." They add that the rate at which the kidney is depleted of iron compared with the depletion rate of the hepatic storage pool might be important.
The Lancet May 10 2003; 361 (9369): 1597-1602. "Effectiveness and safety of ICL670 in iron-loaded patients with thalassaemia: a randomised, double-blind, placebo-controlled, dose-escalation trial"

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