Study on the Pharmacokinetics and Pharmacodynamics of Transdermal Estradiol Gel Administered Repeatedly in Postmenopausal Women

Transdermal administration of estrogen has established its positioning among hormone replacement therapies in menopause. In Divigel® (estradiol hemihydrate gel 0.1%), 17β-estradiol, a body-identical estrogen, is formulated to be absorbed through the skin. This study aimed to provide systematic data on the pharmacokinetics and pharmacodynamics of Divigel to further enable its use in individualized therapies. The study was conducted over a 14-day treatment period using three escalating doses (0.5 mg, 1.0 mg, and 1.5 mg) in ten postmenopausal women. A 3-day or 4-day follow-up period was conducted after each treatment period. Wash-out between the periods was at least 2 weeks. The serum levels of estradiol (E2) and its metabolite estrone (E1) were analyzed, and the therapeutically informative ratio of E2/E1 was calculated. In addition, the temporal course of the excretion of E1, E2, and estriol (E3) in urine was studied. Serum levels of gonadotropins, follicle-stimulating hormone and luteinizing hormone, were measured as pharmacodynamic biomarkers. Serum concentrations of E2 were proportional to dose, and profiles were dose dependent. A steady-state E2 concentration was achieved within 3–5 days of daily administration of 1.0-mg and 1.5-mg doses. After the first and last application, the serum E2/E1 ratio increased clearly above 1.0 within 2–12 hours post-dose, i.e., approximating premenopausal levels, whereas it returned and remained close to parity at steady state, which still is clearly above the measured baseline (menopausal) levels. The urine levels of E1 and E3 were comparable and much higher than E2 urine levels. After the last application on day 14, the average serum concentration values of E2 (calculated as area under the concentration–time curve from time 0 to 24 hours divided by the 24-hour application interval) were 12.4 ± 7.0, 29.7 ± 7.3, and 55.0 ± 33.1 pg/mL at 0.5-mg, 1.0-mg and 1.5-mg doses, respectively. Those fit into the clinically effective concentration range at the doses of 1.0 mg or 1.5 mg in all the subjects. Follicle-stimulating hormone levels were lower after application of Divigel at every dose compared with their pre-dosing baseline. Luteinizing hormone levels also decreased following E2 administration. Treatment was well tolerated, and no safety concerns or skin reactions were observed. Transdermal estradiol treatment with Divigel produced dose-proportional, clinically meaningful serum E2 levels and E2/E1 ratios in postmenopausal women. All administered doses also showed expected hormonal pharmacodynamic effects and were well tolerated. Not applicable in the USA and European Union for a pharmacokinetic study commenced in 1999.