PHARMACOKINETICS OF ESTRADIOL AND ESTRONE FOLLOWING REPEATED ADMINISTRATION OF MENOREST(R), A NEW ESTROGEN TRANSDERMAL DELIVERY SYSTEM, IN MENOPAUSAL WOMEN

The objective of this study was to evaluate the pharmacokinetics of es tradiol and estrone, at steady-state, after repeated applications of M enorest(R) delivering 0.025, 0.050 and 0.100mg estradiol daily, and to determine the plasma concentration/administered dose relationship. It was an open randomised crossover study, with 3 treatment periods of 1 0.5 days separated by two 12-day intervening washout periods. Randomis ation was conducted according to a latin square design. The clinical p art of the study was carried out at CAP (Centre d'Activite Pharmacolog ique), Montpellier, and plasma estradiol and estrone concentrations we re determined at CEPHAC (Centre d'Etudes et de Recherche en Pharmacie Clinique), St Benoit, France. The study included 30 healthy postmenopa usal women, volunteers aged between 42 and 70 years (mean 59.13 +/- 6. 90 years). Each transdermal system dosage was applied for 3 successive 3.5-day wear periods (10.5 days) on the lower abdominal skin. Plasma estradiol and estrone concentrations were measured at steady-state, be fore and after the third application of each transdermal system dosage at regular intervals over 106 hours. Cutaneous tolerance was assessed after each transdermal system removal. After the third application of patches releasing 0.025, 0.050 and 0.100 mg/day, a linear relationshi p was established between the administered dose and the estradiol phar macokinetic parameters [area under the plasma concentration-time curve from time 0 to 84 hours (AUC(0-84h)), maximum plasma concentration (C -max), minimum plasma concentration (C-min) and average plasma concent ration (C-av)]. This relationship did not exist between plasma estrone concentrations and estradiol administered doses, although these conce ntrations increased with the increased dosage. Adverse events were nei ther serious nor unexpected; none required discontinuation of the trea tment, and their incidence was higher with the highest doses. Erythema and skin wrinkling were the most frequent cutaneous reactions - their frequency (related to the number of applications) was increased from 26 to 44% for erythema acid from 2 to 40% for skin wrinkling when the administered dose increased from 0.025 to 0.100 mg/day. It was conclud ed that the linear relationship established between plasma estradiol c oncentrations and administered doses constitutes the basis for the dos age adjustment to the individual needs of postmenopausal women in the range 0.025 to 0.100 mg/day, and allows adjustment of the dose to deli ver the minimum effective level of estrogen.