17 beta-Estradiol delivered by three different matrix patches 50 mu g/day - A three way cross-over study in 21 postmenopausal women

The aim of this study was to investigate the systemic bioavailability and p lasma profiles of 17 beta-estradiol (E-2) after the application of three ma trix patches for the transdermal delivery of E-2: Menorest(TM), Tradelia(TM ), and Estraderm MX(TM) claiming to deliver a dosage of 50 mu g E-2/day. Al l three patches were each worn randomly by 21 postmenopausal women voluntee rs over a 4-day period (i.e. 96 h). Each of the three treatment periods wer e separated by an at least 7 day wash out period according to a randomized, 3-way crossover design. Blood samples were taken from the antecubital vein before and 3, 6, 9, 12, 24, 28, 33, 48, 57, 72, 81, and 96 h after applica tion. E-2 plasma values were determined by a specific direct radioimmunoass ay method. The following pharmacokinetic parameters were evaluated. AUC(0-9 6h), C-max, T-max, C-min, C-average. The time to reach the maximal E-2 valu e of 32 h was the only pharmacokinetic parameter which was identical for al l three patches. Menorest(TM) produced the highest E-2 bioavailability judg ed by the AUC(0-->96h) = 3967.8 +/- 1651.8 pg/ml. C-average = 41.3 +/- 21.3 pg/ml, C-min = 36.8 +/- 8.6 pg/ml. Tradelia(TM) showed statistically not s ignificantly smaller C-average = 38.9 +/- 17.0 pg/ml, AUC(0-->96h) = 3737.9 +/- 1637.6 pg/ml.per h, and C-min = 33.8 +/- 26.7 than Menorest(TM). Estra derm MX(TM) showed lowest E-2 plasma profiles C-max = 38.9 +/- 25.1 pg/ml, C-average = 33.2 +/- 17.1 pg/ml, AUC(0-->96h) = 3192.1 +/- 1646.0 pg/ml per .h. Menorest(TM) showed the smallest fluctuation over the entire test perio d, similar to Estraderm MX(TM), while Tradelia(TM) showed the highest E-2-f luctuation (P < 0.01): Tradelia(TM) exhibited the highest C-max = 48.0 +/- 20.3 pg/ml. When E-2 baseline levels, prior to patch application are subtra cted individually from the produced E-2 plasma level, Estraderm MX(TM) is n ot bioequivalent to Menorest(TM) (P < 0.05). A circadian curve pattern of t he E-2 plasma level was observed for all patches: in the evening higher E-2 plasma level were always detected compared with the morning, however, less pronounced with Estraderm MX(TM). Individual comparison of AUC(0-->96h) of each patch exhibited a large interindividual variability of 2000-8000 pg/m l per h for all three patches but relatively small individual variability: women with high E-2 bioavailability (high responders) maintained high bioav ailability in all applied patches, women identified as low and medium respo nders remained the same regardless of the applied patch. Menorest(TM) produ ced in 2/3 of all postmenopausal women with the highest E-2 bioavailability (AUC(0-->96h)), Tradelia(TM) was found in less than 1/3 (28.6%), and Estra derm(TM) MX in only one postmenopausal woman. Menorest(TM) only produced th e highest reduction in postmenopausal symptoms together with Tradelia(TM) E straderm MX(TM) produced a smaller reduction in postmenopausal symptoms com pared to Menorest(TM) and Tradelia(TM). The observed side-effects were appr oximately equal in all three patches, with a maximum value after 72 h. It can be concluded that the three patches for the transdermal delivery of E-2 claiming to deliver 50 mu g E-2/day differed from each other in their p harmacokinetic performance, although statistically not significant: Menores t(TM) exhibited the highest C-average, AUC and C-min, and the lowest fluctu ation, followed by Tradelia(TM) and Estraderm MX(TM). (C) 1999 Elsevier Sci ence Ireland Ltd. All rights reserved.