STEADY-STATE PHARMACOKINETICS OF ESTRADIOL GEL IN POSTMENOPAUSAL WOMEN - EFFECTS OF APPLICATION AREA AND WASHING

Objective To investigate the effect of cutaneous application area on o estradiol absorption using an oestradiol gel for transdermal use. Furt hermore, the effect of washing of the application site on oestradiol p harmacokinetics was studied. Design Open-label, randomised, three-way cross-over study. Setting A clinical pharmacokinetic research unit. Su bjects Sixteen healthy postmenopausal volunteers. Interventions During three treatment periods, subjects were treated with 1 mg oestradiol ( 1.0 g Divigel(R)/Sandrena(R) 0.1% gel), applied on the thigh to a skin area of 200 cm(2), 400 cm(2), or on an area 'as large as possible'. B lood samples were drawn during steady-state (on days 14-15) immediatel y before application and at regular time intervals thereafter. Main ou tcome measures Serum oestradiol levels were measured for determination of peak concentration (C-max), time to peak concentration (t(max)) an d bioavailability using the area under the time concentration curve (A UC(0-24)). Results Bioavailability from a 200 cm(2) area was 2-fold hi gher than that from the largest possible area (P < 0.05). Oestradiol p eak plasma concentration from a 200 cm(2) area was higher than from th e 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 cm(2) and 400 cm(2) appl ication areas (P < 0.01), but peak plasma concentration from the 200 c m(2) area only (P < 0.01). Time to reach peak plasma concentrations wa s significantly reduced with all three application areas by washing. C onclusion A higher oestradiol absorption was achieved from a smaller a pplication area. No marked differences were observed in the pharmacoki netics between 200 cm(2) and 400 cm(2) application areas, which are th ose recommended for this oestradiol gel preparation.