Steady-state pharmacokinetics of oestradiol gel in post-menopausal women: effects of application area and washing

Objective To investigate the effect of cutaneous application area on oestradiol absorption using an oestradiol gel for transdermal use. Furthermore, the effect of washing of the application site on oestradiol pharmacokinetics was studied. Design Open-label, randomised, three-way cross-over study. Setting A clinical pharmacokinetic research unit. Subjects Sixteen healthy postmenopausal volunteers. Interventions During three treatment periods, subjects were treated with 1 mg oestradiol (1.0 g Divigel®/Sandrena® 0.1% gel), applied on the thigh to a skin area of 200 cm2,400 cm2, or on an area ‘as large as possible’. Blood samples were drawn during steady-state (on days 14–15) immediately before application and at regular time intervals thereafter. Main outcome measures Serum oestradiol levels were measured for determination of peak concentration (Cmax), time to peak concentration (tmax) and bioavailability using the area under the time concentration curve (AUC0–24). Results Bioavailability from a 200 cm2 area was 2-fold higher than that from the largest possible area ((P<0.05)). Oestradiol peak plasma concentration from a 200 cm2 area was higher than from the two larger areas ((P<0.05)), which did not differ significantly from each other. Washing of the application site 30 min after application reduced the bioavailability from both the 200 cm2 and 400 cm2 application areas ((P<0.01)), but peak plasma concentration from the 200 cm2 area only ((P<0.01)). Time to reach peak plasma concentrations was significantly reduced with all three application areas by washing. Conclusion A higher oestradiol absorption was achieved from a smaller application area. No marked differences were observed in the pharmacokinetics between 200 cm2 and 400 cm2 application areas, which are those recommended for this oestradiol gel preparation.