Effect of blood tamoxifen concentrations on surrogate biomarkers in a trial of dose reduction in healthy women
Effect of blood tamoxifen concentrations on surrogate biomarkers in a trial of dose reduction in healthy women
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DOI：
10.1200/jco.1999.17.9.2633
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发表时间：
1999-09-01
影响因子：
45.3
通讯作者：
Lien, EA
中科院分区：
文献类型：
--
作者：
Decensi, A;Gandini, S;Lien, EA
目的：他莫昔芬以20 mg/d给药已被证明可将高危女性的乳腺癌发病率降低50%，但毒性可能限制其广泛使用，特别是在绝经后女性中。因为毒性可能是剂量依赖性的，我们研究了低浓度的他莫昔芬的生物活性，以确定剂量reduction.Patients和方法的可接受性：我们测量了他莫昔芬及其主要代谢物的血液浓度在剂量滴定研究中105名健康妇女（安慰剂，他莫昔芬10我隔日，他莫昔芬10毫克/天，他莫昔芬20毫克/天）。治疗2个月后测量的药物水平与不同疾病的替代生物标志物的变化相关，包括血脂谱、巢细胞计数、纤维蛋白原、抗凝血酶III、骨钙素和胰岛素样生长因子I，这是一种有前途的乳腺癌替代生物标志物。他莫昔芬和N-去甲基他莫昔芬的平均值（+/- SD）（代谢产物X）浓度（ng/mt）与剂量相关，安慰剂组分别为0和0，10 me隔日给药组分别为26.8 +/- 15.1和43.7 +/- 22.5，10 mg/d组为51.2 ± 24.1和90.7 ± 48.0，20 mg/d组为136.0 ± 52.7和230.6 ± 75.0。从方差来看，除血小板计数和甘油三酯水平外，任何药物浓度下生物标志物的变化幅度相当，后者显示出随着他莫昔芬浓度的增加而增加的趋势。结论：血液浓度降低80%似乎并不影响他莫昔芬对心血管或乳腺癌风险生物标志物的活性，事实上可能具有更有利的安全性。需要进行更多的研究以确定这种药物的最合适剂量。(C)1999年，美国临床肿瘤学会。
Purpose: Tamoxifen administered at 20 mg/d has been shown to decrease breast cancer incidence in at-risk women by 50%, but toxicity may limit its broad use, particularly in postmenopausal women. Because toxicity may be dose-dependent, we studied the biologic activity of low concentrations of tamoxifen to determine the plausibility of a dose reduction.Patients and Methods: We measured the blood concentrations of tamoxifen and its main metabolites in a dose titration study in 105 healthy women (placebo, tamoxifen 10 me on alternate days, tamoxifen 10 mg/d, and tamoxifen 20 mg/d). Drug levels measured after 2 months of treatment were correlated with the changes in surrogate biomarkers of different diseases, including lipid profile, brood cell count, fibrinogen, antithrombin ill, osteocalcin, and insulin-like growth factor I, a promising surrogate biomarker of breast cancer.Results: The means (+/- SD) for tamoxifen and N-desmethyltamoxifen (metabolite X) concentrations (ng/mt) were dose-related, being, respectively, 0 and 0 with placebo, 26.8 +/- 15.1 and 43.7 +/- 22.5 with 10 me every other day, 51.2 +/- 24.1 and 90.7 +/- 48.0 with 10 mg/d, and 136.0 +/- 52.7 and 230.6 +/- 75.0 with 20 mg/d of tamoxifen. At variance, the biomarker changes were of comparable magnitude at any drug concentration except for platelet count and triglycerides levels, the latter showing a trend to an increase with increasing tamoxifen concentrations.Conclusion: An 80% reduction in blood concentrations does not seem to affect the activity of tamoxifen on biomarkers of cardiovascular or breast cancer risk and may in fact have a more favorable safety profile. Additional studies are warranted to determine the most appropriate dose of this agent. (C) 1999 by American Society of Clinical Oncology.