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Development of dosage individualization of anti-tumor drugs based on therapeutic drug monitoring and pharmacokinetic-related gene expression

基于治疗药物监测和药代动力学相关基因表达的抗肿瘤药物个体化剂量开发

基本信息

批准号：
17590131
负责人：
MATSUMOTO Mitsuhiro
金额：
$ 2.24万
依托单位：
Kumamoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

项目摘要

Amrubicin, a synthetic 9-aminoanthracycline agent, was recently approved in Japan for treatment of small-cell lung cancer and non-small-cell lung cancer. Amrubicin is converted enzymatically to the C-13 hydroxy metabolite amrubicinol, which is active and possesses a cytotoxicity 10 to 100 times that of the parent drug. The purpose of this study was to charicterize the pharmacokinetics of amrubicin and its active metabolite amrubicinol. Amrubicin was administered on days 1-3 in 16 patients with advanced lung cancer. The pharmacokinetics analysis of amrubicin and amrubicinol was performed by high-performance liquid chromatography. When 45 mg/m amrubicin was administered in a bolus injection once every 24 hours for 3 consecutive days, the areas under the curves (0 to 72 hours) for amrubicin and amrubicinol were 13,490 and 2585 ng.h/mL, respectively. The apparent total clearance (CL_<app>) of amrubicin was 15.4 L/h. The area-under-the-curve ratio of amrubicinol to amrubicin was 15.1 +/-4.6% (mean +/-SD) at doses ranging from 30 to 45 mg/m. Interindividual variability in the enzymatic conversion of amrubicin to amrubicinol was small. In contrast, a large interindividual variability in the CL_<app> of amrubicin was observed (CV = 49.8%). The areas under the curves of amrubicin and amrubicinol seemed to be associated with the severity of hematologic toxicities. There is a possibility that monitoring of the plasma concentrations of amrubicin and amrubicinol may provide an efficient tool for establishing the optimal dosage of amrubicin in each patient. Furthermore, we found that both amrubicin and amrubicinol are substrates of P-gp. Additionally, the antitumor effects of amrubicin might be affected by P-gp in lung cancer cells. Further studies are warranted to clarify the contribution of P-gp in the antitumor activity and pharmacokinetics of amrubicin.

氨柔比星是一种合成的9-氨基蒽环类药物，最近在日本被批准用于治疗小细胞肺癌和非小细胞肺癌。氨柔比星通过酶转化为C-13羟基代谢物氨柔比醇，其具有活性，细胞毒性是母体药物的10至100倍。本研究的目的是研究氨柔比星及其活性代谢物氨柔比醇的药代动力学。16例晚期肺癌患者在第1-3天给予氨柔比星。采用高效液相色谱法对氨柔比星和氨柔比醇进行药代动力学分析。当氨柔比星以45 mg/m2的剂量每24小时一次推注给药连续3天时，氨柔比星和氨柔比醇的曲线下面积（0 - 72小时）分别为13，490和2585 ng.h/mL。氨柔比星的表观总清除率<app>为15.4L/h。在30 - 45 mg/m2剂量范围内，氨柔比星与氨柔比星的曲线下面积比为15.1 +/-4.6%（平均值+/-SD）。氨柔比星酶促转化为氨柔比醇的个体间差异很小。氨柔比星的CL在个体间差异较大<app>（CV = 49.8%）。氨柔比星和氨柔比醇的曲线下面积似乎与血液学毒性的严重程度相关。监测氨柔比星和氨柔比醇的血浆浓度可能为确定每位患者氨柔比星的最佳剂量提供有效工具。此外，我们发现氨柔比星和氨柔比醇都是P-gp的底物。此外，氨柔比星的抗肿瘤作用可能受到肺癌细胞中P-gp的影响。P-gp在氨柔比星抗肿瘤活性和药代动力学中的作用有待进一步研究。