EVALUATION OF THE BIOAVAILABILITY AND DOSE PROPORTIONALITY OF 3 FORMULATIONS OF A COMBINATION ESTROGEN AND PROGESTIN ADHESIVE-BASED MATRIX TRANSDERMAL, DELIVERY SYSTEM

The single-dose and steady-state pharmacokinetics of estradiol (E-2), estrone, and norethindrone acetate (NETA) were examined in three studi es of healthy postmenopausal women after application of a transdermal patch delivering 50/140, 50/250, or 50/400 mu g/d of E-2 and NETA (E-2 /NETA). In a single-dose study, the area under the serum concentration -time curve (AUC) and the maximum serum concentrations (C-max) of E-2 and norethindrone (NET) were 24% and 28% higher, respectively, when th e E-2/NETA 50/250-mu g/d patch was applied to the abdomen compared wit h the buttocks of 18 women. Single and multiple applications of the pa tches containing the three E-2/NETA formulations resulted in the deliv ery of constant serum concentrations of E-2, estrone, and NET at stead y state. Significant differences were observed between E-2/NETA 50/250 mu g/d and E-2/NETA 50/140 and 50/400 mu g/d with regard to average s erum concentrations (C-avg) and AUC at steady-state (AUC(ss)), indicat ing that E-2/NETA 50/140 mu g/d delivers lower serum E-2 concentration s and E-2/NETA 50/400 mu g/d delivers higher serum E-2 concentrations when compared with E-2/NETA 50/250 mu g/d. E-2/NETA 50/250 mu g/d was bioequivalent to E-2 50 mu g/d as evidenced by bioequivalent AUC(ss), C-avg, and C-max estimates. E-2/NETA 50/140 mu g/d delivered approxima tely 6% less E-2, and E-2/NETA 50/400 mu g/d delivered approximately 1 0% more E-2 than E-2 50 mu g/d. The delivery of NET from the three for mulations of E-2/NETA was dose proportional. In summary, all three E-2 /NETA formulations maintained constant serum concentrations of E-2 and NET during the dosing interval.