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Comparison of Pharmacokinetics of a Conjugated Equine Estrogen Preparation (Premarin) and a Synthetic Mixture of Estrogens (C.E.S.) in Postmenopausal Women

Department of Obstetrics and Gynecology, University of Western Ontario, London, Ontario; Department of Obstetrics and Gynecology, University of Toronto, and St. Michael's Hospital, Inner City Health Program, Toronto, Ontario, Canada; bhavnani{at}smh.toronto.on.ca

Jeffrey A. Nisker, MD

Jim Martin, MD

Fatma Aletebi, MD

Lynn Watson, RN

J. Kenneth Milne, MD

Department of Obstetrics and Gynecology, University of Western Ontario, London, Ontario; Department of Obstetrics and Gynecology, University of Toronto, and St. Michael's Hospital, Inner City Health Program, Toronto, Ontario, Canada

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 estrone (E₁), equilin (Eq), 17ß-estradiol (17ß-E₂), 17ß-dihydroequilin (17ß-Eq), ⁸-esterone (⁸-E₁) and ⁸, 17ß-estradiol (⁸, 17ß-E₂) were measured over 72 hours using gas chromatography and mass spectroscopy.

Results: After administration of C.E.S., E₁, Eq, and 17ß-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) of unconjugated and total Eq, and 17ß-Eq were significantly lower after C.E.S., whereas those of E₁ were significantly higher. Although, the t_max values for 17ß-E₂ were lower than the C_max values higher after C.E.S., only the C_max of unconjugated 17ß-E₂ was significantly different after Premarin. Unconjugated and total ⁸-E₁ and its main metabolite, ⁸, 17ß-E₂, 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 E₁, Eq, 17ß-E₂, and 17ß-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 E₁ and total Eq, none of the AUC_t or AUC 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. demonstrate its efficacy, extrapolation of the long-term benefits described for Premarin to C.E.S. would be risky and questionable.

Key Words: Estrone • equilin • 17ß-estradiol • 17ß-dihydroequlin • 8-estrone • bioavailability of conjugated estrogens

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