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

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 × 0.625 mg) of Premarin or C.E.S., plasma concentrations of unconjugated and total estrone (E1), equilin (Eq), 17β-estradiol (17β-E2), 17β-dihydroequilin (17β-Eq), Δ8-esterone (Δ8-E1) and Δ8, 17β-estradiol (Δ8, 17β-E2) were measured over 72 hours using gas chromatography and mass spectroscopy. Results: After administration of C.E.S., E1, Eq, and 17β-Eq appeared in blood at a significantly faster rate (lower tmax) than after Premarin. The rapid appearance of estrogens after C.E.S. was associated with significantly higher (14-61%) Cmax values. In contrast to the high Cmax values, the area under the curve (AUC)∞ of unconjugated and total Eq, and 17β-Eq were significantly lower after C.E.S., whereas those of E1 were significantly higher. Although, the tmax values for 17β-E2 were lower than the Cmax values higher after C.E.S., only the Cmax of unconjugated 17β-E2 was significantly different after Premarin. Unconjugated and total Δ8-E1 and its main metabolite, Δ8, 17β-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 Cmax and tmax values for the unconjugated and total E1, Eq, 17β-E2, and 17β-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 AUCt or AUCα 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.