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

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。地铁苷（GT 56 -252）是一种非常有效的口服铁螯合剂。我们在B型地中海贫血患者中进行总代谢铁平衡研究，其中比较去铁蛋白与去铁醛（DFO）皮下输注的疗效。还正在评价去铁苷的安全性以及各种药理学参数。研究了四种剂量的地铁曲林（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，这对Benedryl有反应。 在11和17 mg/kg剂量下，未观察到显著或药物相关不良事件。在最高剂量（25 mg/kg）下，以8小时间隔分三次给药。测定的药代动力学参数与早期进行的I期研究中观察到的参数一致。关于铁排泄，与所有此类研究一样，存在显著的患者间变异性。剂量高达17 mg/kg时，铁的剂量相关排泄似乎接近平台期，远低于这些患者实现负铁平衡所需的水平。因此，考虑到药物在血流中的半衰期相对较短，我们决定评估分三次给药的较高剂量（25 mg/kg）。多次给药后未观察到显著或一致的药物相关不良事件。铁排泄量增加超过平台期，但低于8.3 mg/kg剂量下预期的三倍。进一步的研究已经被搁置，等待正在进行的II期研究的结果。

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.