Effect of dose on the absorption of estradiol from a transdermal gel

Abstract

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.