Phase I and pharmacokinetic study of amrubicin, a synthetic 9-aminoanthracycline, in patients with refractory or relapsed lung cancer
Phase I and pharmacokinetic study of amrubicin, a synthetic 9-aminoanthracycline, in patients with refractory or relapsed lung cancer
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DOI：
10.1007/s00280-005-0051-2
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发表时间：
2006-03-01
影响因子：
3
通讯作者：
Saito, H
中科院分区：
文献类型：
--
作者：
Okamoto, I;Hamada, A;Saito, H
氨柔比星是一种新的合成9-氨基蒽环类抗生素衍生物，经酶促转化为其C-13羟基代谢产物氨柔比醇，其细胞毒活性是氨柔比星的10-100倍。我们的目的是确定氨柔比星的最大耐受剂量（MTD），并描述氨柔比星和氨柔比醇在既往接受过治疗的难治性或复发性肺癌患者中的药代动力学特征。15例患者静脉注射氨柔比星30、35或40 mg/m2，连续3天，每3周1次，共43个疗程。中性粒细胞减少是主要毒性（4级，67%）。MTD为40 mg/m2，在该剂量下治疗的3名患者中，特定的剂量限制性毒性为持续4天以上的4级中性粒细胞减少症、发热性中性粒细胞减少症或3级心律失常。1例非小细胞肺癌患者显示部分缓解，10例患者病情稳定。氨柔比星和氨柔比醇的血药浓度-时间曲线下面积（AUC）随氨柔比星剂量增加而增加。氨柔比星AUC与氨柔比醇AUC显著相关。因此，对于标准化疗难治性肺癌患者，氨柔比星的II期推荐剂量为35 mg/m2，每日1次，连续3天，每3周一次。
Amrubicin is a novel synthetic 9-aminoanthracycline derivative and is converted enzymatically to its C-13 hydroxy metabolite, amrubicinol, whose cytotoxic activity is 10-100 times that of amrubicin. We aimed to determine the maximum tolerated dose (MTD) of amrubicin and to characterize the pharmacokinetics of amrubicin and amrubicinol in previously treated patients with refractory or relapsed lung cancer. The 15 patients were treated with amrubicin intravenously at doses of 30, 35, or 40 mg/m(2) on three consecutive days every 3 weeks for a total of 43 courses. Neutropenia was the major toxicity (grade 4, 67%). The MTD was 40 mg/m(2), with the specific dose-limiting toxicities being grade 4 neutropenia persisting for > 4 days, febrile neutropenia, or grade 3 arrhythmia in the three patients treated at this dose. A patient with non-small-cell lung cancer showed a partial response, and ten individuals experienced a stable disease. The area under the plasma concentration versus time curve (AUC) for amrubicin and that for amrubicinol increased with amrubicin dose. The amrubicin AUC was significantly correlated with the amrubicinol AUC. The recommended phase II dose of amrubicin for patients with lung cancer refractory to standard chemotherapy is thus 35 mg/m(2) once a day for three consecutive days every 3 weeks.