Comparison of pharmacokinetics of a conjugated equine estrogen preparation(Premarin) and a synthetic mixture of estrogens (CES) in postmenopausal women

Objective: To compare the pharmacokinetics and relative bioavailabilities o f key estrogen components of Premarin (Wyeth-Ayerst, Canada) with those of a generic conjugated estrogen preparation, C.E.S. (synthetic mixture of est rogens; ICN, Montreal, Canada) in healthy postmenopausal women. Methods: We conducted a randomized, single-dose, two-treatment, three-perio d 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-dihyd roequilin (17 beta-Eq), Delta(8)-esterone (Delta 8-E-1) and Delta(8),17 bet a-estradiol (Delta(8),17 beta-E-2) were measured over 72 hours using gas ch romatography 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. T he rapid appearance of estrogens after C.E.S. was associated with significa ntly 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 wer e lower and the C-max values higher after C.E.S., only the C-max of unconju gated 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 d etectable in plasma only after administration of Premarin. The geometric me an ratio (GMR) (C.E.S./Premarin) of bioavailability parameters indicated th at all C-max and t(max) values for the unconjugated and total E-1, Eq, 17 b eta-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%. Simi larly, 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 standar ds of bioequivalence. Conclusions: C.E.S. is not bioequivalent to Premarin. Because C.E.S. also i s not pharmaceutically equivalent to Premarin, it cannot be assumed to be t herapeutically equivalent. Until long-term clinical trials with C.E.S. woul d be risky and questionable. Copyright (C) 2000 by the Society for Gynecolo gic Investigation.