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Comparison of estrogen products
Letters 235
Volume 169, Number I Am J Obstet Gynecol
will be different. Therefore the authors' finding of similar plasma levels of estrone and estradiol is surprising. Are the zero time levels of estrone and estradiol significantly different from the 8-hour levels? 5. The design of the study is inappropriate. A better experimental design with such small numbers of subjects (n = 5 or n = 6) in each group would have been a crossover study. Until the bioequivalence of the three estrogen preparations is rigorously established, as defined by the Food and Drug Administration: the results of the current study should be interpreted with extreme caution. Bhagu R. Bhavnani, PhD, and Anthony Cecutti, MD Department of Obstetrics and Gynecology, University of Toronto and St. Michael's Hospital, 30 Bond St., Toronto, Ontario, Canada M5B
1W8
REFERENCES 1. Bhavnani BR. The saga of the ring-B unsaturated equine estrogens. Endocr Rev 1988;9:319-416. 2. Bhavnani BR, Woolever CA. Interaction of ring-B unsaturated estrogens with estrogen receptors of human endometrium and rat uterus. Steroids 1991;56:201-9. 3. Geola FL, Frumer AM, Tataryn IV, et al. Biological effects of various doses of conjugated equine estrogens in postmenopausal women. J Clin Endocrin Metab 1980,51 :620-5. 4. US Food and Drug Administration. Bioavailability and bioequivalence requirements. Fed Reg 1977;42:1638-53.
Comparison of estrogen products To the Editors: A recent article (Jurgens RW Jr, Downey LJ, Abernethy WD, Cutler NR, Conrad J. A comparison of circulating hormone levels in postmenopausal women receiving hormone replacement therapy. AM J OBSTET GYNECOL 1992;167;459-60) purported to show similar plasma concentrations and clearances of estrone and estradiol in a group of postmenopausal women who received multiple oral doses of esterified estrogens in the form of Estratab, Premarin, and Estratest H.S. products. Close inspection of the data and report, however, reveals possible differences between these products and a number of deficiencies in the design of the study. First, their data in Fig. 1 indicate that the estrone and estradiol concentrations over days 1 through 29 may be about 50% higher in the subjects receiving Estratab, a difference stated not to be statistically significant. Complicating any interpretation of these results is the use of single time points for blood samples (8 ± 2 hours) and the use of parallel treatment groups containing only five or six women. The interindividual variability of estrogen absorption and metabolism is known to be large. For this reason, the Food and Drug Administration guidelines for studies of conjugated estrogens recommend a two-treatment four-sequence, three-period crossover design with 36 subjects. I Without crossover and enrolling only five or six subjects per group, it is no surprise that the study
failed to detect differences. Further, Premarin contains several estrogen compounds, including about 30% equilin sulfate and 1713-dihydroequilin sulfate. 2 Data on these important compounds are not reported. 1713Dihydroequilin, for example, is a potent metabolite of equilin that is present systemically in high concentrations and should be measured." Drug exposure between products is commonly evaluated by comparing bioavailability; the latter is defined as both the "rate and extent of absorption." To fully characterize the concentration-time profile, serial blood samples obtained over either 0 to 48 hours or an entire dosing interval are required with consideration of the maximum value of the plasma concentration, the time of maximum concentration, and calculation of the area under the curve. I The current study relied on 4-week single samples taken at 8 (± 2) hours after dosing. The use of different subjects, different estrogen components, and different products will produce highly variable serum concentration versus time patterns for the measured compounds. 1·4 Any conclusions based on few and single-time-point blood samples could be misleading. Finally, the study used single blood samples at I week after the last dose of each product to indicate that the estrogens were cleared at the same rate with all products. Again, multiple blood samples are needed to define the elimination of any drug, especially compounds with moderate half-life values. Given the inadequate design of this study and the limited data, it is premature of Jurgens et al. to suggest that serum concentrations of the three products are similar. It is unfortunate that Solvay Pharmaceuticals has no bioavailability-type data at present on which to base any comparisons of Estratest with other marketed estrogen products. William J. Jusko, PhD Professor of Pharmaceutics, School of Pharmacy, State University of New York at Buffalo, Buffalo NY 14260
REFERENCES 1. Food and Drug Administration. Guidance conjugated estrogens tablets. Rockville, Maryland: Division of Bioequivalence, Food and Drug Administration, 1991 Aug 21. 2. Bhavnani BF. The saga of the ring-B unsaturated equine estrogens. Endocr Rev 1988;2:396-416. 3. Englund DE, Johansson EDB. Plasma levels of oestrone, oestradiol and gonadotrophins in postmenopausal women after oral and vaginal administration of conjugated oestrogens (Premarin). Br J Obstet Gynaecol 1978;85:957-64. 4. Schindler AE, Bolt HM, Zwirner M, Hochlehnert G, G6ser R. Comparative pharmacokinetics of oestradiol, oestrone, oestrone sulfate and "conjugated oestrogens" after oral administration, ArZIleimitteiforschung 1982;32:787-91.
Reply To the Editors: Both inquiries mention there are numerous components of Pre marin and suggest that more of the components should have been measured in the Solvay study. According to the United States Pharma-
Volume 169, Number I Am J Obstet Gynecol
will be different. Therefore the authors' finding of similar plasma levels of estrone and estradiol is surprising. Are the zero time levels of estrone and estradiol significantly different from the 8-hour levels? 5. The design of the study is inappropriate. A better experimental design with such small numbers of subjects (n = 5 or n = 6) in each group would have been a crossover study. Until the bioequivalence of the three estrogen preparations is rigorously established, as defined by the Food and Drug Administration: the results of the current study should be interpreted with extreme caution. Bhagu R. Bhavnani, PhD, and Anthony Cecutti, MD Department of Obstetrics and Gynecology, University of Toronto and St. Michael's Hospital, 30 Bond St., Toronto, Ontario, Canada M5B
1W8
REFERENCES 1. Bhavnani BR. The saga of the ring-B unsaturated equine estrogens. Endocr Rev 1988;9:319-416. 2. Bhavnani BR, Woolever CA. Interaction of ring-B unsaturated estrogens with estrogen receptors of human endometrium and rat uterus. Steroids 1991;56:201-9. 3. Geola FL, Frumer AM, Tataryn IV, et al. Biological effects of various doses of conjugated equine estrogens in postmenopausal women. J Clin Endocrin Metab 1980,51 :620-5. 4. US Food and Drug Administration. Bioavailability and bioequivalence requirements. Fed Reg 1977;42:1638-53.
Comparison of estrogen products To the Editors: A recent article (Jurgens RW Jr, Downey LJ, Abernethy WD, Cutler NR, Conrad J. A comparison of circulating hormone levels in postmenopausal women receiving hormone replacement therapy. AM J OBSTET GYNECOL 1992;167;459-60) purported to show similar plasma concentrations and clearances of estrone and estradiol in a group of postmenopausal women who received multiple oral doses of esterified estrogens in the form of Estratab, Premarin, and Estratest H.S. products. Close inspection of the data and report, however, reveals possible differences between these products and a number of deficiencies in the design of the study. First, their data in Fig. 1 indicate that the estrone and estradiol concentrations over days 1 through 29 may be about 50% higher in the subjects receiving Estratab, a difference stated not to be statistically significant. Complicating any interpretation of these results is the use of single time points for blood samples (8 ± 2 hours) and the use of parallel treatment groups containing only five or six women. The interindividual variability of estrogen absorption and metabolism is known to be large. For this reason, the Food and Drug Administration guidelines for studies of conjugated estrogens recommend a two-treatment four-sequence, three-period crossover design with 36 subjects. I Without crossover and enrolling only five or six subjects per group, it is no surprise that the study
failed to detect differences. Further, Premarin contains several estrogen compounds, including about 30% equilin sulfate and 1713-dihydroequilin sulfate. 2 Data on these important compounds are not reported. 1713Dihydroequilin, for example, is a potent metabolite of equilin that is present systemically in high concentrations and should be measured." Drug exposure between products is commonly evaluated by comparing bioavailability; the latter is defined as both the "rate and extent of absorption." To fully characterize the concentration-time profile, serial blood samples obtained over either 0 to 48 hours or an entire dosing interval are required with consideration of the maximum value of the plasma concentration, the time of maximum concentration, and calculation of the area under the curve. I The current study relied on 4-week single samples taken at 8 (± 2) hours after dosing. The use of different subjects, different estrogen components, and different products will produce highly variable serum concentration versus time patterns for the measured compounds. 1·4 Any conclusions based on few and single-time-point blood samples could be misleading. Finally, the study used single blood samples at I week after the last dose of each product to indicate that the estrogens were cleared at the same rate with all products. Again, multiple blood samples are needed to define the elimination of any drug, especially compounds with moderate half-life values. Given the inadequate design of this study and the limited data, it is premature of Jurgens et al. to suggest that serum concentrations of the three products are similar. It is unfortunate that Solvay Pharmaceuticals has no bioavailability-type data at present on which to base any comparisons of Estratest with other marketed estrogen products. William J. Jusko, PhD Professor of Pharmaceutics, School of Pharmacy, State University of New York at Buffalo, Buffalo NY 14260
REFERENCES 1. Food and Drug Administration. Guidance conjugated estrogens tablets. Rockville, Maryland: Division of Bioequivalence, Food and Drug Administration, 1991 Aug 21. 2. Bhavnani BF. The saga of the ring-B unsaturated equine estrogens. Endocr Rev 1988;2:396-416. 3. Englund DE, Johansson EDB. Plasma levels of oestrone, oestradiol and gonadotrophins in postmenopausal women after oral and vaginal administration of conjugated oestrogens (Premarin). Br J Obstet Gynaecol 1978;85:957-64. 4. Schindler AE, Bolt HM, Zwirner M, Hochlehnert G, G6ser R. Comparative pharmacokinetics of oestradiol, oestrone, oestrone sulfate and "conjugated oestrogens" after oral administration, ArZIleimitteiforschung 1982;32:787-91.
Reply To the Editors: Both inquiries mention there are numerous components of Pre marin and suggest that more of the components should have been measured in the Solvay study. According to the United States Pharma-