Oral ciclopirox olamine displays biological activity in a phase I study in patients with advanced hematologic malignancies
Oral ciclopirox olamine displays biological activity in a phase I study in patients with advanced hematologic malignancies
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DOI：
10.1002/ajh.23640
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发表时间：
2014-04-01
影响因子：
12.8
通讯作者：
Schimmer, Aaron D.
中科院分区：
文献类型：
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作者：
Minden, Mark D.;Hogge, Donna E.;Schimmer, Aaron D.
抗真菌环吡酮醇胺是一种细胞内的铁络合剂，在体外和体内都具有抗癌活性。我们开发了一种环吡咯胺的口服制剂，并在复发或难治性血液系统恶性肿瘤患者中进行了该药物的首次人类I期研究(试验注册ID：NCT00990587)。用5~80 mg/m(2)环吡酮醇胺口服，每日1次，连续5天，21天为一疗程。在一组患者中进行了药代动力学和药效学配对研究。在定义了环吡酮胺的半衰期后，另一组受试者接受了每天四次的80 mg/m(2)环吡酮醇胺治疗。在整个试验过程中，监测了不良事件和临床反应。23名患者接受了研究治疗。Ciclopirox被迅速吸收和清除，半衰期短。非活性环吡喃葡萄糖醛酸代谢产物的血浆浓度高于环吡喃。从每天一次用大于10 mg/m(2)的环吡酮胺治疗的患者分离的外周血细胞中观察到Survivin的表达被抑制，这表明了该药物的生物活性。每日4次80 mg/m(2)的患者出现剂量限制性胃肠道毒性，每天1次40 mg/m(2)的患者未观察到剂量限制性毒性。观察到两名患者的血液学改善。对于复发或难治性血液系统恶性肿瘤患者，每日口服一次环吡咯胺的耐受性良好，在这类患者中有必要进一步优化给药方案。上午好。J.血醇。：363-368,2014年。(C)2013年威利期刊公司。
The antimycotic ciclopirox olamine is an intracellular iron chelator that has anticancer activity in vitro and in vivo. We developed an oral formulation of ciclopirox olamine and conducted the first-in-human phase I study of this drug in patients with relapsed or refractory hematologic malignancies (Trial registration ID: NCT00990587). Patients were treated with 5-80 mg/m(2) oral ciclopirox olamine once daily for five days in 21-day treatment cycles. Pharmacokinetic and pharmacodynamic companion studies were performed in a subset of patients. Following definition of the half-life of ciclopirox olamine, an additional cohort was enrolled and treated with 80 mg/m(2) ciclopirox olamine four times daily. Adverse events and clinical response were monitored throughout the trial. Twenty-three patients received study treatment. Ciclopirox was rapidly absorbed and cleared with a short half-life. Plasma concentrations of an inactive ciclopirox glucuronide metabolite were greater than those of ciclopirox. Repression of survivin expression was observed in peripheral blood cells isolated from patients treated once daily with ciclopirox olamine at doses greater than 10 mg/m(2), demonstrating biological activity of the drug. Dose-limiting gastrointestinal toxicities were observed in patients receiving 80 mg/m(2) four times daily, and no dose limiting toxicity was observed at 40 mg/m(2) once daily. Hematologic improvement was observed in two patients. Once-daily dosing of oral ciclopirox olamine was well tolerated in patients with relapsed or refractory hematologic malignancies, and further optimization of dosing regimens is warranted in this patient population. Am. J. Hematol. 89:363-368, 2014. (c) 2013 Wiley Periodicals, Inc.