A phase I trial to assess the pharmacology of the new oestrogen receptor antagonist fulvestrant on the endometrium in healthy postmenopausal volunteers
A phase I trial to assess the pharmacology of the new oestrogen receptor antagonist fulvestrant on the endometrium in healthy postmenopausal volunteers
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DOI：
10.1038/sj.bjc.6600644
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发表时间：
2002-12-02
影响因子：
8.8
通讯作者：
Laight, A
中科院分区：
文献类型：
--
作者：
Addo, S;Yates, RA;Laight, A
虽然他莫昔芬的使用与治疗对雌激素敏感的乳腺癌的明显益处相关，但它也表现出与不良事件（包括子宫内膜癌）相关的部分雌激素激动剂活性。氟维司群（“芙仕得”）是一种新型雌激素受体拮抗剂，可下调雌激素受体，无已知的激动剂效应。进行了一项单中心、双盲、随机、平行组试验，以确定氟维司群单独给药和与雌激素炔雌醇联合给药时对女性子宫内膜的直接影响。在为期14天的试验前筛选期后，30名合格的绝经后志愿者随机接受氟维司群250 mg、氟维司群125 mg或匹配的安慰剂单次肌内注射给药。注射后2周，志愿者同时接受2周炔雌醇暴露，20 μ g/天（-1）。在14天筛选期前后测量子宫内膜厚度，并在氟维司群治疗前（以确认恢复至基线）和治疗后第14、28和42天进一步测量。在整个试验期间进行药代动力学和安全性评估。与安慰剂相比，250 mg剂量的氟维司群显著（P=0.0001）抑制雌激素刺激的子宫内膜增厚。在初始14天评估期内，125 mg和250 mg剂量的氟维司群均未显示对子宫内膜的雌激素效应。氟维司群耐受性良好，并降低了炔雌醇相关副作用的发生率。在绝经后晚期乳腺癌女性的临床试验中评价的相同剂量水平下，氟维司群（250 mg）是一种抗雌激素，在健康绝经后女性的子宫内膜中没有激动剂活性的证据。(C)2002年英国癌症研究。
While tamoxifen use is associated with clear benefits in the treatment of hormone-sensitive breast cancer, it also exhibits partial oestrogen agonist activity that is associated with adverse events, including endometrial cancer. Fulvestrant ('Faslodex') is a new oestrogen receptor antagonist that downregulates the oestrogen receptor and has no known agonist effect This single-centre, double-blind, randomised, parallel-group trial was conducted to determine the direct effects of fulvestrant on the female endometrium when given alone and in combination with the oestrogen, ethinyloestradiol. Following a 14-day, pretrial screening period, 30 eligible postmenopausal volunteers were randomised to receive fulvestrant 250 mg, fulvestrant 125 mg or matched placebo administered as a single intramuscular injection. Two weeks postinjection, volunteers received 2-weeks concurrent exposure to ethinyloestradiol 20 mug day(-1), Endometrial thickness was measured before and after the 14-day screening period with further measurements precose (to confirm a return to baseline) and on days 14, 28 and 42 posttreatment with fulvestrant. Pharmacokinetic and safety assessments were performed throughout the trial. Fulvestrant at a dose of 250 mg significantly (P=0.0001) inhibited the oestrogen-stimulated thickening of the endometrium compared with placebo. Neither the 125 mg nor 250 mg doses of fulvestrant demonstrated oestrogenic effects on the endometrium over the initial 14-day assessment period. Fulvestrant was well tolerated and reduced the incidence of ethinyloestradiol-related side effects. At the same dose level that is being evaluated in clinical trials of postmenopausal women with advanced breast cancer, fulvestrant (250 mg) is an antioestrogen with no evidence of agonist activity in the endometrium of healthy postmenopausal women. (C) 2002 Cancer Research UK.