Phase I and pharmacokinetic study of the topoisomerase II catalytic inhibitor fostriecin
Phase I and pharmacokinetic study of the topoisomerase II catalytic inhibitor fostriecin
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DOI：
10.1038/sj.bjc.6690141
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发表时间：
1999-02-01
影响因子：
8.8
通讯作者：
de Vries, EGE
中科院分区：
文献类型：
--
作者：
de Jong, RS;Mulder, NH;de Vries, EGE
我们对拓扑异构酶II催化抑制剂fostriecin进行了I期和药代动力学研究。Fostriecin在第1-5天以4周间隔静脉内施用60分钟。20例患者的剂量从2 mg m（-2）day（-1）递增至20 mg m（-2）day（-1）。采用高效液相色谱-紫外检测法分析药物的药代动力学，体外检测给药期间收集的血浆对替尼泊苷耐药小细胞肺癌（SCLC）细胞系的生长抑制作用。主要毒性为河水转氨酶升高（最大常见毒性标准（CTC）4级）和血清肌酐升高（最大CTC 2级）。随着剂量的增加，这些变化仅出现有限的增加，通常在给药期间恢复，并且完全可逆。在20 mg/m2时，1例患者丙氨酸氨基转移酶（ALT）升高的持续时间是剂量限制性的，其他常见毒性为1-2级恶心/呕吐、发热和轻度疲劳。平均磷霉素血浆半衰期为0.36 h（初始; 95% CI，0-0.76 h）和1.51 h（终末; 95% GI，0.41-2.61。高频在血浆和尿液中检测到代谢产物，最可能是去磷酸化fostriecin。未观察到肿瘤反应，但患者体内达到的血浆浓度不足以诱导体外显著的生长抑制。尚未达到最大耐受剂量（MTD），因为在20 mg m-2剂量水平停止了药物供应。然而，进一步升级似乎是可能的，并且有必要达到潜在有效的药物水平。Fostriecin的血浆半衰期较短，应考虑更长的输注时间。
We conducted a phase I and pharmacokinetic study of the topoisomerase II catalytic inhibitor fostriecin. Fostriecin was administered intravenously over 60 min on days 1-5 at 4-week intervals. Dose was escalated from 2 mg m(-2) day(-1) to 20 mg m(-2) day(-1) in 20 patients. Drug pharmacokinetics was analysed with high performance liquid chromatography with UV-detection, Plasma collected during drug administration was tested in vitro for growth inhibition of a teniposide-resistant small-cell lung cancer (SCLC) cell line. The predominant toxicities were elevated river transaminases (maximum common toxicity criteria (CTC) grade 4) and serum creatinine (maximum CTC grade 2). These showed only a limited increase with increasing doses, often recovered during drug administration and were fully reversible. Duration of elevated alanine-amino transferase (ALT) was dose-limiting in one patient at 20 mg m(-2), Other frequent toxicities were grade 1-2 nausea/vomiting, fever and mild fatigue. Mean fostriecin plasma half-life was 0.36 h (initial; 95% CI, 0-0.76 h) and 1.51 h (terminal; 95% GI, 0.41-2.61. hf. A metabolite, most probably dephosphorylated fostriecin, was detected in plasma and urine. No tumour responses were observed, but the plasma concentrations reached in the patients were insufficient to induce significant growth inhibition in vitro. The maximum tolerated dose (MTD) has not been reached, because drug supply was stopped at the 20 mg m-2 dose level. However, further escalation seems possible and is warranted to achieve potentially effective drug levels. Fostriecin has a short plasma half-life and longer duration of infusion should be considered.