Pharmacokinetics and pharmacodynamics of three dosages of oestriol after continuous vaginal ring administration for 21 days in healthy, postmenopausal women

Abstract

Evaluation of the oestriol pharmacokinetics, pharmacodynamics and safety in healthy, postmenopausal women under treatment with a vaginal ring with continuous delivery rates of 0.125 (Test 1), 0.250 (Test 2) or 0.500mgday(-1) (Test 3) for 21days. Thirty-one subjects received a single application of Test 1, 2 or 3. The oestriol plasma concentration was determined by liquid chromatography coupled tandem mass spectrometry. Follicle-stimulating hormone (FSH), luteinizing hormone (LH) and sex hormone-binding globulin serum concentrations, and maturation value (MV) and vaginal pH were assessed to describe the pharmacodynamics. Adverse events, local tolerability and endometrial thickness were evaluated to determine safety. The 90% confidence interval of the coefficient/slope was 0.5997-1.174% for area under the curve of plasma concentration (AUC) up to the last measurement, 0.5838-1.115% for AUC extrapolated to infinity and 0.2408-0.943% for maximum plasma concentration. Dose proportionality could not be rejected for AUC, but a deviation from proportionality was statistically significant for maximum plasma concentration. The FSH and LH curves showed a decrease that was more pronounced with higher delivery rates; however, sex hormone-binding globulin did not present this behaviour. A treatment effect on MV and vaginal pH was comparable for all formulations. All products showed increase in MV (70-80%) and the distribution of parabasal, intermediate and superficial cells showed a shift towards superficial cells. The vaginal pH values markedly decreased under treatment. The effect on endometrial thickness was not dose-dependent. All formulations released sufficient oestriol to trigger the maximum local effect. However, there was no difference between formulations regarding surrogate parameters for clinical efficacy. A dose-dependency; however, was clearly demonstrated for FSH and LH. The product was well tolerated and safe