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Objectives: To compare the absorption of estradiol from a transdermal gel and a novel matrix-type patch and to study the variability in absorption. Methods: Twenty-four healthy postmenopausal women were treated in an open, randomized, cross-over study for 18 days with 1.0 mg estradiol daily as a transdermal gel and a transdermal patch releasing estradiol 50 μg/24 h without a wash-out between the periods. Venous blood samples for estradiol pharmacokinetics were taken on the 15th and 18th study days of the gel period and during the 15th–18th study days during the patch period. Results: There was no significant difference in peak estradiol level or area under the estradiol time–concentration curve between the gel and the patch. However, trough estradiol concentration was significantly lower and fluctuation higher with the patch. Estradiol time–concentration curves on the 15th and 18th study days with the gel were almost superimposable. A significant difference was observed in peak estradiol levels, whereas area under the curve or trough estradiol level did not differ between the 15th and 18th study days with the gel. Inter- and intra-individual coefficients of variability were around 30% for peak estradiol level and area under the curve, except for the intra-individual coefficient of variability for area under the curve (21%) for the gel. The total coefficient of variability for area under the curve was 35% for the gel and 39% for the patch. Conclusions: A daily 1.0 mg estradiol dose as a transdermal gel seems to correspond with a matrix-type patch releasing 50 μg estradiol daily in the extent of estradiol absorption. High variability was associated with both treatments, and both the variabilities within and between the subjects were high with the gel. Wider than generally applied confidence limits should be applied for bioequivalence testing of transdermal estradiol formulations.

Objectives: To compare oestradiol and oestrone concentrations and bioavailability after a single dose and at a steady state during oral oestradiol valerate, transdermal oestradiol gel and transdermal oestradiol patch treatments. Methods: Two open, randomised, cross-over studies were conducted. In the first study, 12 healthy postmenopausal women received 1.5 mg oestradiol as a transdermal gel or a 2 mg oestradiol valerate tablet daily for 14 days. In the second study, 15 postmenopausal women were treated for 18 days with 1.5 mg oestradiol gel or a transdermal patch releasing oestradiol 50 μg/24 h (replaced every 72 h). Venous blood samples for serum oestradiol and oestrone measurements with RIA were taken until 24 or 72 h after the first and last doses. Results: The tablet and the transdermal gel yielded similar serum oestradiol profiles with a peak concentration 4–5 h after administration. The patch resulted in relatively stable oestradiol levels during the mid third of the wearing time whereas much lower levels were observed in the beginning and towards the end. There was no difference in the fluctuation between the peak and trough oestradiol levels between the gel (56 or 67%) and the tablet (54%) while the fluctuation was greater with the patch (89%). The bioavailability of oestradiol from the gel was 61% as compared with the tablet and 109% as compared with the patch. The gel was not bioequivalent with the tablet or the patch. Conclusions: The doses used of the transdermal gel and the patch roughly corresponded to each other with regard to the amount of oestradiol absorbed whereas the bioavailability from the tablet was significantly higher than from the gel. The lack of bioequivalence, the different serum oestradiol profiles and the large intersubject variability suggest that individual dose adjustments may be needed when changing administration form.

Objectives: To study whether ageing affects the pharmacokinetics of estradiol valerate (E 2 V) or medroxyprogesterone acetate (MPA) in postmenopausal women. Methods: Forty-six postmenopausal women from two essentially similar pharmacokinetic studies were divided into three age categories: under 60 years ( n =15), between 60 and 65 years ( n =18) and over 65 years ( n =13). They all were treated for 12 days or 14 days with four galenically identical tablets containing combinations of 1 mg or 2 mg E 2 V and 2.5 mg or 5 mg MPA. The studies followed an open, randomised cross-over design with no washout between the periods. Serum estradiol and MPA concentrations were measured at steady state on study day 12 or 14 of each period. Results: No statistically significant differences were observed in the peak concentration ( C max ), time to peak ( t max ), AUC or elimination half-life for estradiol or MPA between the different age groups. In spite of the lack of statistical significance the AUC was on an average 1.6-fold and C max 1.40-fold higher in the oldest group of women than in the youngest group and age was found significant as a continuous variable for AUC and C max for MPA but not for estradiol. Conclusions: The results suggest that there would be no significant changes in the pharmacokinetics of estradiol between women under 60 and over 65 years of age. However, a significant trend towards higher MPA concentrations and bioavailability was observed with increasing age. The results suggest that from the pharmacokinetic point of view the relationship between estradiol and MPA dose to be used in elderly could be different from that in younger postmenopausal women, while no pharmacokinetic reasons to use lower estradiol doses in the elderly were observed.

Objectives : To study whether dose adjustments in transdermal estradiol gel treatment would result in proportional changes in estradiol bioavailability and concentrations. Methods : In an open study, 23 healthy postmenopausal women were treated consecutively with 0.5, 1.0 and 1.5 mg estradiol daily as a transdermal gel. Each dose was given for 16 days. Venous blood samples for serum estradiol and estrone measurements with RIA were taken at steady state on the 16th study day. From these concentrations, pharmacokinetic parameters for estradiol were calculated and corrected to correspond to equal dose by dividing the values by the dose. Results : Area under the estradiol time–concentration curve and peak estradiol level increased linearily and dose-proportionally with daily estradiol doses of 0.5–1.5 mg. This was shown by lack of significant differences in the dose-corrected parameters. However, the 90% confidence intervals between the doses were outside the commonly accepted levels for bioequivalence. Peak estradiol level was clearer and occurred earlier with the highest 1.5 mg estradiol dose, while more stable estradiol levels were seen with the lowest 0.5 mg estradiol dose. Conclusions : The amount of estradiol on a certain skin area seems to be the determining factor in absorption. With higher estradiol doses, the absorption will be accelerated with a clearer peak estradiol level. The linear and dose proportional absorption indicates that flexible dose adjustments within the dose range of 0.5–1.5 mg estradiol daily can be made with an anticipated effect in estradiol bioavailability and concentrations.