Conjugated estrogens bioinequivalence: comparison of four products in postmenopausal women

The bioequivalence of four conjugated estrogens tablets USP was compared by measurement of seven estrogens or estrogen metabolites in the urine during steady-state dosing in postmenopausal women. Two studies compared three generic products with the innovator's product. The urinary excretion of 17 alpha-dihydroequilin, 17 alpha-dihydroequilenin, and 17 alpha-estradiol were significantly greater in all cases with the innovator's product than with the generic products. Statistically significant differences between products were observed occasionally for other components. The generic products thus were bioinequivalent to the innovator's product, although all products essentially met current compendial specifications. A third study observed no significant differences between three batches of the innovator's product for the seven components. Total conjugated estrogens excretion of all products at the steady state was essentially equal and correlated with neither disintegration time nor dissolution half-time. Bioinequivalence between products is discussed in relation to the need for an improved USP conjugated estrogens monograph. Evidence suggesting the metabolism of a fraction of dosed estrone, equilin, and 17 alpha-dihydroequilin to 17 beta-estradiol, 17 beta-dihydorequilim, and 17 alpha-dihydroequilenin, respectively, is presented.