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

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。去铁蛋白（GT56-252）是一种潜在的口服铁螯合剂。我们正在进行b型地中海贫血患者的总代谢铁平衡研究，其中将去铁蛋白与皮下输注的Desferal （DFO）的疗效进行比较。去铁蛋白的安全性以及各种药理学参数也正在评估中。研究了四种剂量的去铁胺（4.5、6.75、11、17和25 mg/kg）。在两个较低剂量下，一些患者出现瘙痒和发红，这是对bendryl的反应。在11和17 mg/kg的剂量下，没有注意到明显的或与药物相关的不良事件。在最高剂量（25mg/kg）时，每8小时给药3次。所确定的药代动力学参数与早期进行的I期研究中观察到的一致。关于铁排泄，在所有这类研究中，患者之间存在显著的差异。在这些患者中，剂量高达17 mg/kg的铁排泄量似乎正在接近平台期，远低于达到铁负平衡所需的水平。因此，考虑到药物在血液中的半衰期相对较短，我们决定评估更高的剂量（25mg /kg），分三次给药。多次给药未发现显著或一致的药物相关不良事件。铁排泄量高于高原水平，但在8.3 mg/kg的剂量下不到预期的三倍。进一步的研究已被搁置，等待正在进行的第二阶段研究的结果。

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.