IRON BALANCE STUDY OF DFO AND GT56-252 IN PATIENTS WITH THALASSEMIA

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Deferitrin (GT56-252) is a potentillay useful orally effective iron-chelating agent. We are conduction total metabolic iron balance studies in patients with B-thalassemia wherein the efficacy of deferitrin is being compared with that of Desferal (DFO) infused subcutaneously. The safety of deferitrin is also being evaluated, together with various pharmacological parameters. Four doses of deferitrim (4.5, 6.75, 11, 17 and 25 mg/kg) have been studied. At the two lower doses, some patients experienced itching and redness which responded to Benedryl. At doses of 11 and 17 mg/kg, no significant or drug-related adverse events were noted. At the highest dose (25mg/kg) the drug was given in three divided doses at 8-hour intervals. The pharmacokinetic parameters determined were in line with those observed in the phase I studies conducted earlier. With regard to iron excretion there was significant patient-to-patient variability as in all such studies. The dose-related excretion of iron at doses up to 17 mg/kg appeared to be approaching a plateau that was well below that needed to achieve negative iron balance in these patients. Accordingly, given the relatively short half-life of the drug in the bloodstream, we decided to evaluate a higher dose (25 mg/kg) administerd in three divided doses. No significant or consistent drug-related adverse events were noted upon multiple dosing. Iron excretion increased above that of the plateau but was less than three times that expected at a dose of 8.3 mg/kg. Further studies have been placed on hold pending eh outcome of ongoing phase II studies.