Comparison of pharmacokinetics of a conjugated equine estrogen preparation (Premarin) and a synthetic mixture of estrogens (CES) in postmenopausal women
Comparison of pharmacokinetics of a conjugated equine estrogen preparation (Premarin) and a synthetic mixture of estrogens (CES) in postmenopausal women
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DOI：
10.1016/s1071-5576(00)00049-6
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发表时间：
2000-05-01
期刊：
影响因子：
--
通讯作者：
Milne, JK
中科院分区：
文献类型：
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作者：
Bhavnani, BR;Nisker, JA;Milne, JK
目的：为了比较倍美力（Wyeth-Ayerst，加拿大）的关键雌激素组分与一般结合雌激素制剂的药代动力学和相对生物利用度，C.E.S.方法：我们在41名绝经后妇女中进行了一项随机、单剂量、两种治疗、三个阶段的交叉研究。口服倍美力（2 x 0.625 mg）或C.E.S.后，未结合雌酮和总雌酮（E-1）、马烯雌酮（Eq）、17 β-雌二醇的血浆浓度（17 β-E-2），17 β-二氢马烯雌酮（17 β-Eq），Delta（8）-Eq使用气相色谱法和质谱法在72小时内测量了C.E.S.（Delta 8-E-1）和Delta（8），17 β-雌二醇（Delta（8），17 β-E-2）。E-1、Eq和17 β-Eq在血液中的出现速度明显快于倍美力后（t（max）较低）。子宫内膜异位症后雌激素的迅速出现。与显著较高（14 - 61%）的C-max值相关。与高C-max值相反，C.E.S.后未结合总Eq和17 β-Eq的曲线下面积（AUC）（无穷大）显著降低，而E-1则显著高于E-1。尽管C.E.S.后17 β-E-2的t（max）值较低，C-max值较高，只有未结合的17 β-E-2的C-max在倍美力后显著不同。未结合和总Delta 8-E1及其主要代谢产物Delta（8），17 β-E-2仅在倍美力给药后在血浆中可检测到。几何平均值比（GMR）（C.E.S./倍美力）的生物利用度参数表明，未结合和总E-1、Eq、17 β-E-2和17 β-Eq的所有C-max和t（max）值均超出了两种产品GMR的90%置信区间在80%和125%范围内的法规要求。同样，除了总E-1和总Eq外，其余雌激素的AUC（t）或AUC（alpha）均不符合生物等效性的监管标准。与倍美力不具有生物等效性。因为C.E.S.也不与倍美力具有药学等效性，因此不能假设其在治疗上具有等效性。直到C.E.S.的长期临床试验会很危险也很可疑版权所有（C）2000由妇科调查协会。
Objective: To compare the pharmacokinetics and relative bioavailabilities of key estrogen components of Premarin (Wyeth-Ayerst, Canada) with those of a generic conjugated estrogen preparation, C.E.S. (synthetic mixture of estrogens; ICN, Montreal, Canada) in healthy postmenopausal women.Methods: We conducted a randomized, single-dose, two-treatment, three-period crossover study in 41 postmenopausal women. After an oral dose (2 x 0.625 mg) of Premarin or C.E.S., plasma concentrations of unconjugated and total estron (E-1), equilin (Eq), 17 beta-estradiol (17 beta-E-2), 17 beta-dihydroequilin (17 beta-Eq), Delta(8)-esterone (Delta 8-E-1) and Delta(8),17 beta-estradiol (Delta(8),17 beta-E-2) were measured over 72 hours using gas chromatography and mass spectroscopy.Results: After administration of C.E.S., E-1, Eq and 17 beta-Eq appeared in blood at a significantly faster rate (lower t(max)) than after Premarin. The rapid appearance of estrogens after C.E.S. was associated with significantly higher (14 - 61%) C-max values. In contrast to the high C-max values, the area under the curve (AUC)(infinity) of unconjugated with the total Eq, and 17 beta-Eq were significantly lower after C.E.S., whereas those of E-1 were significantly higher. Although, the t(max) values for 17 beta-E-2 were lower and the C-max values higher after C.E.S., only the C-max of unconjugated 17 beta-E-2 was significantly different after Premarin. Unconjugated and total Delta 8-E1 and its main metabolite, Delta(8), 17 beta-E-2, were detectable in plasma only after administration of Premarin. The geometric mean ratio (GMR) (C.E.S./Premarin) of bioavailability parameters indicated that all C-max and t(max) values for the unconjugated and total E-1, Eq, 17 beta-E-2, and 17 beta-Eq fell outside the regulatory requirement that the 90% confidence intervals of GMRs of two products be within 80% and 125%. Similarly, with the exception of total E-1 and total Eq, none of the AUC(t) or AUC(alpha) of the remaining estrogens meets the required regulatory standards of bioequivalence.Conclusions: C.E.S. is not bioequivalent to Premarin. Because C.E.S. also is not pharmaceutically equivalent to Premarin, it cannot be assumed to be therapeutically equivalent. Until long-term clinical trials with C.E.S. would be risky and questionable. Copyright (C) 2000 by the Society for Gynecologic Investigation.